|
Growth inhibition of Candida parapsilosis after 24 hrs by broth dilution assay
|
Candida parapsilosis
|
0.79
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin in combination with amphotericin B against Candida parapsilosis.
Year : 2007
Volume : 51
Issue : 3
First Page : 941
Last Page : 945
Authors : Barchiesi F, Spreghini E, Tomassetti S, Giannini D, Scalise G.
Abstract : Candida parapsilosis has emerged as an important nosocomial pathogen. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of caspofungin (CAS) in combination with amphotericin B (AMB) against three clinical isolates of C. parapsilosis. Although there was a significant reduction of the MIC of one or both drugs used in combination, an indifferent interaction (fractional inhibitory concentration index greater than 0.50 and less than or equal to 4.0) was observed in 100% of cases. This finding was confirmed by killing curve studies. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were often significantly greater than those produced by each drug alone. Antagonism was never observed. In a murine model of systemic candidiasis, CAS at either 0.25 or 1 mg/kg/day combined with AMB at 1 mg/kg/day was significantly more effective than each single drug at reducing the colony counts in kidneys. Higher doses of the echinocandin (i.e., 5 and 10 mg/kg/day) combined with the polyene did not show any advantage over CAS alone. Overall, our study showed a positive interaction of CAS and AMB against C. parapsilosis.
|
Growth inhibition of Candida parapsilosis after 48 hrs by broth dilution assay
|
Candida parapsilosis
|
1.17
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin in combination with amphotericin B against Candida parapsilosis.
Year : 2007
Volume : 51
Issue : 3
First Page : 941
Last Page : 945
Authors : Barchiesi F, Spreghini E, Tomassetti S, Giannini D, Scalise G.
Abstract : Candida parapsilosis has emerged as an important nosocomial pathogen. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of caspofungin (CAS) in combination with amphotericin B (AMB) against three clinical isolates of C. parapsilosis. Although there was a significant reduction of the MIC of one or both drugs used in combination, an indifferent interaction (fractional inhibitory concentration index greater than 0.50 and less than or equal to 4.0) was observed in 100% of cases. This finding was confirmed by killing curve studies. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were often significantly greater than those produced by each drug alone. Antagonism was never observed. In a murine model of systemic candidiasis, CAS at either 0.25 or 1 mg/kg/day combined with AMB at 1 mg/kg/day was significantly more effective than each single drug at reducing the colony counts in kidneys. Higher doses of the echinocandin (i.e., 5 and 10 mg/kg/day) combined with the polyene did not show any advantage over CAS alone. Overall, our study showed a positive interaction of CAS and AMB against C. parapsilosis.
|
Antifungal activity against Aspergillus fumigatus by broth microdilution method
|
Aspergillus fumigatus
|
95.54
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Concentration-dependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: analysis by a new response surface model.
Year : 2007
Volume : 51
Issue : 6
First Page : 2053
Last Page : 2064
Authors : Meletiadis J, Stergiopoulou T, O'Shaughnessy EM, Peter J, Walsh TJ.
Abstract : Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (</=0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.
|
Antifungal activity against Aspergillus flavus by broth microdilution method
|
Aspergillus flavus
|
95.54
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Concentration-dependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: analysis by a new response surface model.
Year : 2007
Volume : 51
Issue : 6
First Page : 2053
Last Page : 2064
Authors : Meletiadis J, Stergiopoulou T, O'Shaughnessy EM, Peter J, Walsh TJ.
Abstract : Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (</=0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.
|
Antifungal activity against Aspergillus terreus by broth microdilution method
|
Aspergillus terreus
|
95.54
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Concentration-dependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: analysis by a new response surface model.
Year : 2007
Volume : 51
Issue : 6
First Page : 2053
Last Page : 2064
Authors : Meletiadis J, Stergiopoulou T, O'Shaughnessy EM, Peter J, Walsh TJ.
Abstract : Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (</=0.20 mg/liter) and at intermediate concentrations of caspofungin (0.95 to 14.88 mg/liter), whereas antagonism (median interaction indices of 1.17 to 1.80) was found at higher concentrations of voriconazole and amphotericin B. Ternary plot and interaction surface analysis further revealed the complexity of these concentration-dependent interactions. With increasing concentrations of amphotericin B, the synergistic interactions of voriconazole-caspofungin double combination decreased while the antagonistic interactions increased. A similar effect was observed when voriconazole was added to the double combination of amphotericin B and caspofungin. In conclusion, the new nonlinear mixture-amount response surface modeling of the triple antifungal combination demonstrated a net antagonism or synergy against Aspergillus species depending upon drug concentrations and species.
|
Antifungal activity against Candida glabrata 05-761 isolate in presence of 5% human serum after 24 hrs by broth microdilution method
|
Candida glabrata
|
0.29
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
Year : 2007
Volume : 51
Issue : 5
First Page : 1616
Last Page : 1620
Authors : Wiederhold NP, Najvar LK, Bocanegra R, Molina D, Olivo M, Graybill JR.
Abstract : In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.
|
Antifungal activity against Candida glabrata 05-62 isolate in presence of 5% human serum after 24 hrs by broth microdilution method
|
Candida glabrata
|
1.4
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
Year : 2007
Volume : 51
Issue : 5
First Page : 1616
Last Page : 1620
Authors : Wiederhold NP, Najvar LK, Bocanegra R, Molina D, Olivo M, Graybill JR.
Abstract : In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.
|
Antifungal activity against Candida glabrata 05-761 isolate after 22 hrs by XTT assay
|
Candida glabrata
|
1.1
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
Year : 2007
Volume : 51
Issue : 5
First Page : 1616
Last Page : 1620
Authors : Wiederhold NP, Najvar LK, Bocanegra R, Molina D, Olivo M, Graybill JR.
Abstract : In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.
|
Antifungal activity against Candida glabrata 05-62 isolate after 22 hrs by XTT assay
|
Candida glabrata
|
1.2
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
Year : 2007
Volume : 51
Issue : 5
First Page : 1616
Last Page : 1620
Authors : Wiederhold NP, Najvar LK, Bocanegra R, Molina D, Olivo M, Graybill JR.
Abstract : In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.
|
Antifungal activity against Candida glabrata 05-62 isolate in presence of 5% human serum after 22 hrs by XTT assay
|
Candida glabrata
|
1.4
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.
Year : 2007
Volume : 51
Issue : 5
First Page : 1616
Last Page : 1620
Authors : Wiederhold NP, Najvar LK, Bocanegra R, Molina D, Olivo M, Graybill JR.
Abstract : In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.
|
Inhibition of glucan synthase in Candida albicans 36082 assessed as incorporation of [3H]uridine diphosphoglucose
|
Candida albicans
|
0.0003301
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans 36082 assessed as incorporation of [3H]uridine diphosphoglucose in presence of 10% serum
|
Candida albicans
|
0.001325
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans 36082 assessed as incorporation of [3H]uridine diphosphoglucose in presence of 20% serum
|
Candida albicans
|
0.002077
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans 36082 assessed as incorporation of [3H]uridine diphosphoglucose in presence of 50% serum
|
Candida albicans
|
0.006225
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus R21
|
Aspergillus fumigatus
|
0.0016
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus R21 in presence of 10% human serum
|
Aspergillus fumigatus
|
0.0027
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus R21 in presence of 20% human serum
|
Aspergillus fumigatus
|
0.0036
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus R21 in presence of 50% human serum
|
Aspergillus fumigatus
|
0.0103
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus MF5668
|
Aspergillus fumigatus
|
0.0011
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus MF5668 in presence of 10% human serum
|
Aspergillus fumigatus
|
0.001
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus MF5668 in presence of 20% human serum
|
Aspergillus fumigatus
|
0.0032
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus MF5668 in presence of 50% human serum
|
Aspergillus fumigatus
|
0.0048
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus ATCC 13073
|
Aspergillus fumigatus
|
0.002
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus ATCC 13073 in presence of 10% human serum
|
Aspergillus fumigatus
|
0.0028
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus ATCC 13073 in presence of 20% human serum
|
Aspergillus fumigatus
|
0.0059
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Aspergillus fumigatus ATCC 13073 in presence of 50% human serum
|
Aspergillus fumigatus
|
0.0094
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 90028
|
Candida albicans
|
0.0003
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 90028 in presence of 10% human serum
|
Candida albicans
|
0.0013
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 90028 in presence of 20% human serum
|
Candida albicans
|
0.0021
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 90028 in presence of 50% human serum
|
Candida albicans
|
0.0063
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 36082
|
Candida albicans
|
0.0009
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 36082 in presence of 10% human serum
|
Candida albicans
|
0.0028
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 36082 in presence of 20% human serum
|
Candida albicans
|
0.0053
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans ATCC 36082 in presence of 50% human serum
|
Candida albicans
|
0.0087
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans SC5314
|
Candida albicans
|
0.0147
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans SC5314 in presence of 10% human serum
|
Candida albicans
|
0.027
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans SC5314 in presence of 20% human serum
|
Candida albicans
|
0.0369
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of glucan synthase in Candida albicans SC5314 in presence of 50% human serum
|
Candida albicans
|
0.0805
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Serum differentially alters the antifungal properties of echinocandin drugs.
Year : 2007
Volume : 51
Issue : 6
First Page : 2253
Last Page : 2256
Authors : Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS.
Abstract : Antifungal efficacies of the echinocandin drugs caspofungin, micafungin, and anidulafungin were reduced significantly in the presence of 50% human serum, which yielded nearly equivalent MICs or minimum effective concentrations against diverse Candida spp. and Aspergillus spp. Consistent with a direct drug interaction, serum decreased the sensitivity of glucan synthase to echinocandin drugs.
|
Inhibition of FKS1 from Candida krusei 98 isolate
|
Pichia kudriavzevii
|
0.0068
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase.
Year : 2007
Volume : 51
Issue : 5
First Page : 1876
Last Page : 1878
Authors : Kahn JN, Garcia-Effron G, Hsu MJ, Park S, Marr KA, Perlin DS.
Abstract : A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080K, in FKS1. The resulting Phe655-->Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.
|
Inhibition of FKS1 T2080K mutant from Candida krusei 100 isolate
|
Pichia kudriavzevii
|
3.942
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Acquired echinocandin resistance in a Candida krusei isolate due to modification of glucan synthase.
Year : 2007
Volume : 51
Issue : 5
First Page : 1876
Last Page : 1878
Authors : Kahn JN, Garcia-Effron G, Hsu MJ, Park S, Marr KA, Perlin DS.
Abstract : A Candida krusei strain from a patient with acute myelogenous leukemia that displayed reduced susceptibility to echinocandin drugs contained a heterozygous mutation, T2080K, in FKS1. The resulting Phe655-->Cys substitution altered the sensitivity of glucan synthase to echinocandin drugs, consistent with a common mechanism for echinocandin resistance in Candida spp.
|
Inhibition of wild-type 1,3-beta-D-glucan synthase KU80delta from Aspergillus fumigatus assessed as incorporation of [3H]glucose
|
Aspergillus fumigatus
|
0.00091
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus.
Year : 2007
Volume : 51
Issue : 11
First Page : 4174
Last Page : 4176
Authors : Rocha EM, Garcia-Effron G, Park S, Perlin DS.
Abstract : An S678P substitution in Fks1p, the major subunit of glucan synthase, was sufficient to confer echinocandin resistance in Aspergillus fumigatus. The equivalent mutation in Candida spp. has been implicated in echinocandin resistance. This work demonstrates that modification of Fks1p is a conserved mechanism for echinocandin resistance in pathogenic fungi.
|
Inhibition of 1,3-beta-D-glucan synthase EMFR-S678P mutant from Aspergillus fumigatus assessed as incorporation of [3H]glucose
|
Aspergillus fumigatus
|
0.1097
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus.
Year : 2007
Volume : 51
Issue : 11
First Page : 4174
Last Page : 4176
Authors : Rocha EM, Garcia-Effron G, Park S, Perlin DS.
Abstract : An S678P substitution in Fks1p, the major subunit of glucan synthase, was sufficient to confer echinocandin resistance in Aspergillus fumigatus. The equivalent mutation in Candida spp. has been implicated in echinocandin resistance. This work demonstrates that modification of Fks1p is a conserved mechanism for echinocandin resistance in pathogenic fungi.
|
Inhibition of 1,3-beta-D-glucan synthase EMFR-S678P/WT mutant from Aspergillus fumigatus assessed as incorporation of [3H]glucose
|
Aspergillus fumigatus
|
0.00012
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : A Ser678Pro substitution in Fks1p confers resistance to echinocandin drugs in Aspergillus fumigatus.
Year : 2007
Volume : 51
Issue : 11
First Page : 4174
Last Page : 4176
Authors : Rocha EM, Garcia-Effron G, Park S, Perlin DS.
Abstract : An S678P substitution in Fks1p, the major subunit of glucan synthase, was sufficient to confer echinocandin resistance in Aspergillus fumigatus. The equivalent mutation in Candida spp. has been implicated in echinocandin resistance. This work demonstrates that modification of Fks1p is a conserved mechanism for echinocandin resistance in pathogenic fungi.
|
Inhibition of metabolite production in Aspergillus fumigatus isolate 06-067-1639 assessed as inhibition of malate and fumarate production at 2 to 4 ug/ml
|
Aspergillus fumigatus
|
20.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of caspofungin on metabolite profiles of Aspergillus species determined by nuclear magnetic resonance spectroscopy.
Year : 2007
Volume : 51
Issue : 11
First Page : 4077
Last Page : 4084
Authors : Plummer R, Bodkin J, Power D, Pantarat N, Bubb WA, Kuchel PW, Sorrell TC.
Abstract : Invasive aspergillosis remains a potentially life-threatening infection, the incidence of which is increasing. Current methods used to determine the susceptibilities of Aspergillus strains to antifungal drugs are often unreliable. Nuclear magnetic resonance (NMR) spectroscopy can identify the metabolic complement of microorganisms while monitoring nutrient utilization from the incubation medium. We used 600-MHz (1)H NMR spectroscopy to monitor the metabolic responses of five Aspergillus species cultured in RPMI 1640-2% glucose-morpholinepropanesulfonate buffer to various concentrations of the antifungal drugs amphotericin B (AMB) and caspofungin. The metabolic endpoint (MEP) was determined from nutrient and metabolite resonances, measured as a function of the drug concentration, and was defined as a > or =50% reduction in nutrient consumption or metabolite production. MICs were evaluated by a modification of Clinical and Laboratory Standards Institute broth microdilution method M27-A, and minimal effective concentrations (MECs) were determined by microscopic examination of fungal hyphae. For AMB, the MEPs coincided with the MICs. For caspofungin, the MEPs agreed with the MECs for several Aspergillus strains, but the effect of drug pressure was more complex for others. Expansion of the MEP definition to include any significant changes in metabolite production resulted in agreement with the MEC in most cases. Paradoxical metabolic responses were observed for several Aspergillus strains at either high or low caspofungin concentrations and for one Aspergillus terreus strain with AMB. NMR spectroscopy proved to be a powerful tool for detecting the subtle effects of drug pressure on fungal metabolism and has the potential to provide an alternative method for determining the susceptibilities of Aspergillus species to antifungal drugs.
|
Antifungal activity against Candida albicans M61 grown as biofilm assessed as maximum inhibition of biofilm metabolic activity at 2 mg/liter after 24 hrs by XTT assay relative to control
|
Candida albicans
|
30.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Differential activities of newer antifungal agents against Candida albicans and Candida parapsilosis biofilms.
Year : 2008
Volume : 52
Issue : 1
First Page : 357
Last Page : 360
Authors : Katragkou A, Chatzimoschou A, Simitsopoulou M, Dalakiouridou M, Diza-Mataftsi E, Tsantali C, Roilides E.
Abstract : The activities of voriconazole, posaconazole, caspofungin, and anidulafungin against Candida albicans and Candida parapsilosis biofilms were evaluated. In contrast to planktonic cells, the MICs for voriconazole and posaconazole for the biofilms of the two species were high (>or=256 and >64 mg/liter, respectively) but relatively low for the echinocandins caspofungin and anidulafungin (<or=1 and <or=2 mg/liter, respectively).
|
Antifungal activity against Candida albicans GDH2346 grown as biofilm assessed as maximum inhibition of biofilm metabolic activity at 2 mg/liter after 24 hrs by XTT assay relative to control
|
Candida albicans
|
30.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Differential activities of newer antifungal agents against Candida albicans and Candida parapsilosis biofilms.
Year : 2008
Volume : 52
Issue : 1
First Page : 357
Last Page : 360
Authors : Katragkou A, Chatzimoschou A, Simitsopoulou M, Dalakiouridou M, Diza-Mataftsi E, Tsantali C, Roilides E.
Abstract : The activities of voriconazole, posaconazole, caspofungin, and anidulafungin against Candida albicans and Candida parapsilosis biofilms were evaluated. In contrast to planktonic cells, the MICs for voriconazole and posaconazole for the biofilms of the two species were high (>or=256 and >64 mg/liter, respectively) but relatively low for the echinocandins caspofungin and anidulafungin (<or=1 and <or=2 mg/liter, respectively).
|
Antifungal activity against Candida albicans ATCC 3153 assessed as death stimulation in vitro pharmacokinetic-pharmacodynamic model
|
Candida albicans
|
0.000251
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mechanism-based pharmacokinetic-pharmacodynamic models of in vitro fungistatic and fungicidal effects against Candida albicans.
Year : 2008
Volume : 52
Issue : 3
First Page : 937
Last Page : 943
Authors : Venisse N, Grégoire N, Marliat M, Couet W.
Abstract : Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) models describing the fungistatic activity of fluconazole and the fungicidal activity of caspofungin were developed using dynamic in vitro models. Antifungal-drug pharmacokinetics was simulated in vitro, assuming a one-compartment model with an elimination half-life of 3 h and using a wide (1 to 10,000) range of initial concentrations. The number of CFUs over time was determined for up to 31 h and used for PK-PD modeling. A model incorporating first-order natural growth and natural death, plus a maximum number of viable Candida cells, was used to characterize Candida growth in the absence of a drug. Fluconazole was considered to inhibit Candida growth and caspofungin to stimulate Candida death according to an Emax pharmacodynamic model. The data were analyzed with Nonmem, using a population approach. A good fit of the data was obtained with satisfactory estimates of PK-PD parameters, especially with drug concentrations producing 50% of the maximal effect: 50% inhibitory concentrations for fluconazole growth inhibition and 50% effective concentrations for caspofungin death stimulation. In conclusion, mechanistic PK-PD models were successfully developed to describe, respectively, the fungistatic and fungicidal activities of fluconazole and caspofungin in vitro. These models provide much better information on the drug effects over time than the traditional PK-PD index based on MICs. However, they need to be further characterized.
|
Antifungal activity against Candida albicans CA5685 by spectrophotometry
|
Candida albicans
|
0.59
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Isobolographic analysis of pharmacodynamic interactions between antifungal agents and ciprofloxacin against Candida albicans and Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 6
First Page : 2196
Last Page : 2204
Authors : Stergiopoulou T, Meletiadis J, Sein T, Papaioannidou P, Tsiouris I, Roilides E, Walsh TJ.
Abstract : Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 microg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis.
|
Antifungal activity against Aspergillus fumigatus AF2350 by spectrophotometry
|
Aspergillus fumigatus
|
28.79
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Isobolographic analysis of pharmacodynamic interactions between antifungal agents and ciprofloxacin against Candida albicans and Aspergillus fumigatus.
Year : 2008
Volume : 52
Issue : 6
First Page : 2196
Last Page : 2204
Authors : Stergiopoulou T, Meletiadis J, Sein T, Papaioannidou P, Tsiouris I, Roilides E, Walsh TJ.
Abstract : Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 microg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis.
|
Inhibition of Candida tropicalis ATCC 750 wild type FKS
|
Candida tropicalis
|
0.00233
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida tropicalis CT-C1 FKS1 T227C mutant
|
Candida tropicalis
|
0.06128
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida glabrata ATCC 90030 wild type FKS
|
Candida glabrata
|
0.00192
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida glabrata CG-C2 FKS1 T1885C mutant
|
Candida glabrata
|
12.78
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida glabrata CG-C3 FKS2 T1987C mutant
|
Candida glabrata
|
16.88
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida albicans ATCC 90028 wild type FKS
|
Candida albicans
|
0.0005
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida albicans 177 FKS1 T1922C mutant
|
Candida albicans
|
1.091
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Inhibition of Candida albicans 205 FKS1 T1933C mutant
|
Candida albicans
|
0.2454
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Novel FKS mutations associated with echinocandin resistance in Candida species.
Year : 2010
Volume : 54
Issue : 5
First Page : 2225
Last Page : 2227
Authors : Garcia-Effron G, Chua DJ, Tomada JR, DiPersio J, Perlin DS, Ghannoum M, Bonilla H.
Abstract : We studied three clinical isolates of Candida spp. (one C. tropicalis isolate and two C. glabrata isolates) from patients with invasive candidiasis. The first isolate emerged during echinocandin treatment, while the others emerged after the same treatment. These strains harbored an amino acid substitution in Fksp never linked before with reduced echinocandin susceptibility in C. tropicalis or in C. glabrata. The molecular mechanism of reduced susceptibility was confirmed using a 1,3-beta-D-glucan synthase inhibition assay.
|
Antifungal activity against Trichophyton rubrum ATCC MYA-4438 by CLSI method
|
Trichophyton rubrum
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Trichophyton mentagrophytes ATCC 9533 by CLSI method
|
Trichophyton mentagrophytes
|
300.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Trichophyton mentagrophytes ATCC MYA-4439 by CLSI method
|
Trichophyton mentagrophytes
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Aspergillus fumigatus ATCC 90906 after 5 days by CLSI method
|
Aspergillus fumigatus
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Cryptococcus neoformans ATCC 66031 after 72 hrs by CLSI method
|
Cryptococcus neoformans
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Cryptococcus neoformans ATCC 90113 after 72 hrs by CLSI method
|
Cryptococcus neoformans
|
400.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida tropicalis ATCC 750 after 48 hrs by CLSI method
|
Candida tropicalis
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida parapsilosis ATCC 22019 after 48 hrs by CLSI method
|
Candida parapsilosis
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida krusei ATCC 6258 after 48 hrs by CLSI method
|
Pichia kudriavzevii
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida glabrata ATCC 90030 after 48 hrs by CLSI methodCandida glabrata
|
Candida glabrata
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Fluconazole resistant Candida albicans clinical isolate 17 after 48 hrs by CLSI method
|
Candida albicans
|
40.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Fluconazole resistant Candida albicans clinical isolate 1 after 48 hrs by CLSI method
|
Candida albicans
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida albicans ATCC 200955 after 48 hrs by CLSI method
|
Candida albicans
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida albicans ATCC 90028 after 48 hrs by CLSI method
|
Candida albicans
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Inhibition of Candida parapsilosis ATCC 22019 glucan synthase by assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.02121
ug.mL-1
|
|
Inhibition of Candida parapsilosis ATCC 22019 glucan synthase by assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
47.99
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida parapsilosis H4 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.07919
ug.mL-1
|
|
Inhibition of Candida parapsilosis H4 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
3.93
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida parapsilosis H5 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.01253
ug.mL-1
|
|
Inhibition of Candida parapsilosis H5 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
6.01
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida orthopsilosis H10 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
0.05816
ug.mL-1
|
|
Inhibition of Candida orthopsilosis H10 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
4.29
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida orthopsilosis 981224 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
0.07526
ug.mL-1
|
|
Inhibition of Candida orthopsilosis 981224 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
7.4
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida metapsilosis am-2006-0113 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
0.04028
ug.mL-1
|
|
Inhibition of Candida metapsilosis am-2006-0113 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
76.9
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida metapsilosis 960161 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
0.02515
ug.mL-1
|
|
Inhibition of Candida metapsilosis 960161 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
80.45
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Saccharomyces cerevisiae BY4742 glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
0.06554
ug.mL-1
|
|
Inhibition of Saccharomyces cerevisiae BY4742 glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
183.94
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Saccharomyces cerevisiae BY4742-FKS1P649A mutant glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
1.329
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of FKS1 deficient Saccharomyces cerevisiae BY4742 glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
2.97
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida albicans Sc5314 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.00388
ug.mL-1
|
|
Inhibition of Candida albicans Sc5314 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.95
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida albicans ATCC 90028 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.00052
ug.mL-1
|
|
Inhibition of Candida albicans ATCC 90028 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.46
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida albicans ATCC 36082 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.0006
ug.mL-1
|
|
Inhibition of Candida albicans ATCC 36082 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
291.67
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida albicans M122 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.07948
ug.mL-1
|
|
Inhibition of Candida albicans M122 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
18.95
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida glabrata ATCC 90030 glucan synthase assessed as [3H]UDPG incorporation
|
Candida glabrata
|
0.00312
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Inhibition of Candida glabrata T51916 glucan synthase assessed as [3H]UDPG incorporation
|
Candida glabrata
|
0.1575
ug.mL-1
|
|
Inhibition of Candida glabrata T51916 glucan synthase assessed as [3H]UDPG incorporation
|
Candida glabrata
|
194.5
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : A naturally occurring proline-to-alanine amino acid change in Fks1p in Candida parapsilosis, Candida orthopsilosis, and Candida metapsilosis accounts for reduced echinocandin susceptibility.
Year : 2008
Volume : 52
Issue : 7
First Page : 2305
Last Page : 2312
Authors : Garcia-Effron G, Katiyar SK, Park S, Edlind TD, Perlin DS.
Abstract : Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.
|
Antifungal activity against Candida albicans ATCC 32354 after 48 hrs by CLSI method
|
Candida albicans
|
70.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida albicans ATCC 14053 after 48 hrs by CLSI method
|
Candida albicans
|
50.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Antifungal activity against Candida albicans ATCC 60193 after 48 hrs by CLSI method
|
Candida albicans
|
30.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Potent in vitro antifungal activities of naturally occurring acetylenic acids.
Year : 2008
Volume : 52
Issue : 7
First Page : 2442
Last Page : 2448
Authors : Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, Elsohly HN, Manly SP, Clark AM.
Abstract : Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C(16) to C(20): 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 muM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 mumol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.
|
Inhibition of Candida tropicalis ATCC 750 glucan synthase subunit FKS1p at monophasic kinetics
|
Candida tropicalis
|
0.002331
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T7 blood stream isolate glucan synthase subunit FKS1p at monophasic kinetics
|
Candida tropicalis
|
0.007652
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T3 blood stream isolate glucan synthase subunit FKS1p with FLTLS/PLRDP mutant at monophasic kinetics
|
Candida tropicalis
|
0.000306
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T3 blood stream isolate glucan synthase subunit FKS1p with FLTLS/PLRDP mutant at biphasic kinetics
|
Candida tropicalis
|
0.3696
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T19 blood stream isolate glucan synthase subunit FKS1p with FLTLS/PLRDP mutant at monophasic kinetics
|
Candida tropicalis
|
0.000296
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T19 blood stream isolate glucan synthase subunit FKS1p with FLTLS/PLRDP mutant at biphasic kinetics
|
Candida tropicalis
|
0.2636
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida tropicalis T26 blood stream isolate glucan synthase subunit FKS1p with LLTLSLRDP mutant at monophasic kinetics
|
Candida tropicalis
|
0.07688
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida albicans ATCC 90028 glucan synthase at monophasic kinetics
|
Candida albicans
|
0.0005
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida albicans 205 glucan synthase subunit FKS1p FLTLPLRDP mutant at monophasic kinetics
|
Candida albicans
|
0.2454
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies.
Year : 2008
Volume : 52
Issue : 11
First Page : 4181
Last Page : 4183
Authors : Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS.
Abstract : We identified three cases of C. tropicalis strains causing breakthrough fungemia in allogeneic stem cell recipients receiving caspofungin prophylaxis and treatment. Three genetically unrelated isolates with high echinocandin MICs were identified. Each strain carried a characteristic mutation conferring an amino acid substitution within Fks1p hot spot 1.
|
Inhibition of Candida albicans SC5314 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans SC5314
|
0.00388
ug.mL-1
|
|
Inhibition of Candida albicans SC5314 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans SC5314
|
2.97
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 36082 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.0009
ug.mL-1
|
|
Inhibition of Candida albicans 36082 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.95
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 90028 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.0005
ug.mL-1
|
|
Inhibition of Candida albicans 90028 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.46
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 1002 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00175
ug.mL-1
|
|
Inhibition of Candida albicans 1002 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
6.26
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 3107 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00362
ug.mL-1
|
|
Inhibition of Candida albicans 3107 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
8.79
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 3795 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00144
ug.mL-1
|
|
Inhibition of Candida albicans 3795 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
4.67
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 119 1,3-beta-D-glucan synthase subunit FKS1p T1921C mutant
|
Candida albicans
|
0.01003
ug.mL-1
|
|
Inhibition of Candida albicans 119 1,3-beta-D-glucan synthase subunit FKS1p T1921C mutant
|
Candida albicans
|
4.92
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 177 1,3-beta-D-glucan synthase subunit FKS1p T1922C mutant
|
Candida albicans
|
1.091
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 2762 1,3-beta-D-glucan synthase subunit FKS1p T1922C mutant
|
Candida albicans
|
0.91
ug.mL-1
|
|
Inhibition of Candida albicans 2762 1,3-beta-D-glucan synthase subunit FKS1p T1922C mutant
|
Candida albicans
|
498.93
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 205 1,3-beta-D-glucan synthase subunit FKS1p T1933C mutant
|
Candida albicans
|
0.2454
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 5415 1,3-beta-D-glucan synthase subunit FKS1p T1933C mutant
|
Candida albicans
|
0.6981
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 89 1,3-beta-D-glucan synthase subunit FKS1p C1934A mutant
|
Candida albicans
|
2.075
ug.mL-1
|
|
Inhibition of Candida albicans 89 1,3-beta-D-glucan synthase subunit FKS1p C1934A mutant
|
Candida albicans
|
860.0
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 85 1,3-beta-D-glucan synthase subunit FKS1p C1934T mutant
|
Candida albicans
|
0.4591
ug.mL-1
|
|
Inhibition of Candida albicans 85 1,3-beta-D-glucan synthase subunit FKS1p C1934T mutant
|
Candida albicans
|
519.33
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 149 1,3-beta-D-glucan synthase subunit FKS1p G1942T mutant
|
Candida albicans
|
0.06822
ug.mL-1
|
|
Inhibition of Candida albicans 149 1,3-beta-D-glucan synthase subunit FKS1p G1942T mutant
|
Candida albicans
|
200.0
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 122 1,3-beta-D-glucan synthase subunit FKS1p C1946A mutant
|
Candida albicans
|
0.08266
ug.mL-1
|
|
Inhibition of Candida albicans 122 1,3-beta-D-glucan synthase subunit FKS1p C1946A mutant
|
Candida albicans
|
291.67
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 121 1,3-beta-D-glucan synthase subunit FKS1p G4082A mutant
|
Candida albicans
|
0.03372
ug.mL-1
|
|
Inhibition of Candida albicans 121 1,3-beta-D-glucan synthase subunit FKS1p G4082A mutant
|
Candida albicans
|
308.0
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 194 1,3-beta-D-glucan synthase subunit FKS1p C1934T/G4082R mutant
|
Candida albicans
|
0.5307
ug.mL-1
|
|
Inhibition of Candida albicans 194 1,3-beta-D-glucan synthase subunit FKS1p C1934T/G4082R mutant
|
Candida albicans
|
466.89
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans 90 1,3-beta-D-glucan synthase subunit FKS1p G4082R mutant
|
Candida albicans
|
0.02043
ug.mL-1
|
|
Inhibition of Candida albicans 90 1,3-beta-D-glucan synthase subunit FKS1p G4082R mutant
|
Candida albicans
|
148.15
ng/ml
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans A15 1,3-beta-D-glucan synthase subunit FKS1p T1933Y mutant
|
Candida albicans
|
0.2181
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida albicans A15-10 1,3-beta-D-glucan synthase subunit FKS1p T1933C mutant
|
Candida albicans
|
0.3224
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints.
Year : 2009
Volume : 53
Issue : 1
First Page : 112
Last Page : 122
Authors : Garcia-Effron G, Park S, Perlin DS.
Abstract : A detailed kinetic characterization of echinocandin inhibition was performed for mutant 1,3-beta-d-glucan synthase enzymes from clinical isolates of Candida albicans with nine different FKS1 mutations resulting in high MICs. Among 14 mutant Fks1p enzymes studied, the kinetic parameters 50% inhibitory concentration and K(i) increased 50-fold to several thousandfold relative to those for the wild type. Enzymes with mutations at Ser645 (S645P, S645Y, and S645F) within hot spot 1 showed the most prominent decrease in sensitivity, while those with mutations at the N- and C-terminal ends of hot spot 1 generally retained greater sensitivity to all three drugs. Kinetic inhibitions by caspofungin, micafungin, and anidulafungin were comparable among the fks1 mutant enzymes, although absolute values did vary with specific mutations. Amino acid substitutions in Fks1p did not alter K(m) values, although some mutations decreased the V(max). Given the association of FKS1 mutations with clinical resistance, an evaluation of the kinetic parameters for the inhibition of mutant 1,3-beta-D-glucan synthase as a function of the MIC enabled an independent evaluation of the recently adopted susceptibility breakpoint for echinocandin drugs. Overall, a breakpoint MIC of >or=2 microg/ml for caspofungin captured nearly 100% of fks1 C. albicans strains when a kinetic inhibition rise threshold of <or=50-fold for the K(i) was used as a measure of susceptibility. A similar MIC breakpoint for micafungin and anidulafungin was less inclusive, and a projected MIC of >or=0.5 microg/ml was required for >95% coverage of clinical isolates. However, when MIC determinations were performed in the presence of 50% serum, all fks1 mutants showed MIC values of >or=2 microg/ml for the three echinocandin drugs. The 1,3-beta-D-glucan synthase kinetic inhibition data support the proposed susceptibility breakpoint for caspofungin in C. albicans, but a lower susceptibility breakpoint (<or=0.5 microg/ml) may be more appropriate for anidulafungin and micafungin. Overall, the data indicate that MIC testing with caspofungin may serve as a surrogate marker for resistance among the class of echinocandin drugs.
|
Inhibition of Candida glabrata ATCC 90030 wild type 1,3-beta-D-glucan synthase
|
Candida glabrata
|
0.00192
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 218 wild type 1,3-beta-D-glucan synthase
|
Candida glabrata
|
0.00311
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 3168 wild type 1,3-beta-D-glucan synthase
|
Candida glabrata
|
0.00179
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 42997 1,3-beta-D-glucan synthase Fks1p F625S mutant/wild type Fks2p
|
Candida glabrata
|
0.6978
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 5847 1,3-beta-D-glucan synthase Fks1p S629P mutant/wild type Fks2p
|
Candida glabrata
|
4.987
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 21900 1,3-beta-D-glucan synthase Fks1p D632G mutant/wild type Fks2p
|
Candida glabrata
|
0.7563
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 3169 1,3-beta-D-glucan synthase Fks1p D632E mutant/wild type Fks2p
|
Candida glabrata
|
0.8445
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 42971 1,3-beta-D-glucan synthase Fks1p D632Y mutant/Fks2p R1377STOP mutant
|
Candida glabrata
|
5.248
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 31498 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p F659 deletion mutant
|
Candida glabrata
|
0.1172
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 234 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p F659V mutant
|
Candida glabrata
|
0.1153
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 41026 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p F659S mutant
|
Candida glabrata
|
1.064
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 3830 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p S663P mutant
|
Candida glabrata
|
5.115
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 41400 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p D666G mutant
|
Candida glabrata
|
0.5066
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 42031 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p D666E mutant
|
Candida glabrata
|
0.2579
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 51916 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p P667T mutant
|
Candida glabrata
|
0.1662
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of Candida glabrata isolate 5416 1,3-beta-D-glucan synthase wild type Fks1p/Fks2p W1375L mutant
|
Candida glabrata
|
0.6084
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-beta-D-glucan synthase: implication for the existing susceptibility breakpoint.
Year : 2009
Volume : 53
Issue : 9
First Page : 3690
Last Page : 3699
Authors : Garcia-Effron G, Lee S, Park S, Cleary JD, Perlin DS.
Abstract : Thirteen Candida glabrata strains harboring a range of mutations in hot spot regions of FKS1 and FKS2 were studied. The mutations were linked to an echinocandin reduced susceptibility phenotype. Sequence alignments showed that 11 out of the 13 mutants harbored a mutation in FKS1 or FKS2 not previously implicated in echinocandin reduced susceptibility in C. glabrata. A detailed kinetic characterization demonstrated that amino acid substitutions in Fks1p and Fks2p reduced drug sensitivity in mutant 1,3-beta-D-glucan synthase by 2 to 3 log orders relative to that in wild-type enzyme. These mutations were also found to reduce the catalytic efficiency of the enzyme (Vmax) and to influence the relative expression of FKS genes. In view of the association of FKS mutations and reduced susceptibility of 1,3-beta-D-glucan synthase, an evaluation of the new CLSI echinocandin susceptibility breakpoint was conducted. Only 3 of 13 resistant fks mutants (23%) were considered anidulafungin or micafungin nonsusceptible (MIC > 2 microg/ml) by this criterion. In contrast, most fks mutants (92%) exceeded a MIC of >2 microg/ml with caspofungin. However, when MIC determinations were performed in the presence of 50% serum, all C. glabrata fks mutants showed MICs of > or = 2 microg/ml for the three echinocandin drugs. As has been observed with Candida albicans, the kinetic inhibition parameter 50% inhibitory concentration may be a better predictor of FKS-mediated resistance. Finally, the close association between FKS1/FKS2 hot spot mutations provides a basis for understanding echinocandin resistance in C. glabrata.
|
Inhibition of wild type Candida albicans MY1055 1,3-beta-D-glucan synthase using UDP[6,3H]-glucose as substrate after 60 mins by liquid scintillation counting analysis
|
Candida albicans
|
0.24
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins.
Year : 2013
Volume : 23
Issue : 11
First Page : 3253
Last Page : 3256
Authors : Singh SB, Herath K, Kahn JN, Mann P, Abruzzo G, Motyl M.
Abstract : Echinocandins and pneumocandins are classes of lipocyclohexapeptides that are broad spectrum antifungal agents. They inhibit fungal specific 1,3-β-glucan synthase activity which is an essential component of the fungal cell wall. Chemical modifications of these two leads have produced three clinical agents namely caspofungin, micafungin and anidulafungin. The presence of hydroxy-glutamine versus threonine and unsaturated linear fatty acid versus branched chain saturated fatty acid differentiate the two classes of compounds with profound differences in their hemolytic properties. In the current study, we have replaced the side chain of the cyclohexapeptides with a common aromatic heterocyclic acyl side chain and compared the biological activities of the cores head-to-head and for the first time demonstrated the role played by the acyl chain and the hydroxy-glutamine for the antifungal potency.
|
Antifungal activity against Aspergillus fumigatus ATCC 46645 assessed as growth inhibition after 24 hrs by checkerboard method
|
Aspergillus fumigatus
|
33.0
nM
|
|
Journal : J. Nat. Prod.
Title : Cyclic colisporifungin and linear cavinafungins, antifungal lipopeptides isolated from Colispora cavincola.
Year : 2015
Volume : 78
Issue : 3
First Page : 468
Last Page : 475
Authors : Ortíz-López FJ, Monteiro MC, González-Menéndez V, Tormo JR, Genilloud O, Bills GF, Vicente F, Zhang C, Roemer T, Singh SB, Reyes F.
Abstract : Colisporifungin (1), a cyclic depsilipopeptide structurally related to the aselacins, and cavinafungins A and B, two linear peptides, were isolated from liquid culture broths of the hitherto unstudied fungus Colispora cavincola using a Candida albicans whole-cell assay as well as a bioassay to detect compounds potentiating the antifungal activity of caspofungin. The structural elucidation, including the absolute configuration of the new molecules, was accomplished using a combination of spectroscopic and chemical techniques, including 1D and 2D NMR, HRMS, and Marfey's analysis. The cyclic peptide colisporifungin displayed a strong potentiation of the growth inhibitory effect of caspofungin against Aspergillus fumigatus and, to a lesser extent, against Candida albicans. The linear peptides displayed broad-spectrum antifungal activities inhibiting growth of Candida species (MIC values 0.5-4 μg/mL) as well as A. fumigatus with a prominent inhibition of 8 μg/mL.
|
Cytotoxicity against human HeLa cells after 48 hrs by SRB assay
|
Homo sapiens
|
100.0
ug.mL-1
|
|
Journal : J. Nat. Prod.
Title : Antifungal Quinoline Alkaloids from Waltheria indica.
Year : 2016
Volume : 79
Issue : 2
First Page : 300
Last Page : 307
Authors : Cretton S, Dorsaz S, Azzollini A, Favre-Godal Q, Marcourt L, Ebrahimi SN, Voinesco F, Michellod E, Sanglard D, Gindro K, Wolfender JL, Cuendet M, Christen P.
Abstract : Chemical investigation of a dichloromethane extract of the aerial parts of Waltheria indica led to the isolation and characterization of five polyhydroxymethoxyflavonoids, namely, oxyanin A (1), vitexicarpin (3), chrysosplenol E (4), flindulatin (5), 5-hydroxy-3,7,4'-trimethoxyflavone (6), and six quinolone alkaloids, waltheriones M-Q (2, 7, 8, 10, 11) and 5(R)-vanessine (9). Among these, compounds 2, 7, 8, 10, and 11 have not yet been described in the literature. Their chemical structures were established by means of spectroscopic data interpretation including (1)H and (13)C, HSQC, HMBC, COSY, and NOESY NMR experiments and UV, IR, and HRESIMS. The absolute configurations of the compounds were established by ECD. The isolated constituents and 10 additional quinoline alkaloids previously isolated from the roots of the plant were evaluated for their in vitro antifungal activity against the human fungal pathogen Candida albicans, and 10 compounds (7, 9, 11-16, 18, 21) showed growth inhibitory activity on both planktonic cells and biofilms (MIC ≤ 32 μg/mL). Their spectrum of activity against other pathogenic Candida species and their cytotoxicity against human HeLa cells were also determined. In addition, the cytological effect of the antifungal isolated compounds on the ultrastructure of C. albicans was evaluated by transmission electron microscopy.
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Inhibition of beta-1,3-glucan synthase in Candida albicans MY1055 microsomal membrane assessed as inhibition of TCA-insoluble material formation using UDP-[3H]-glucose as substrate incubated for 2 hrs in presence of GTP by radioactivity-based assay
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Candida albicans
|
0.001
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Ibrexafungerp: An orally active β-1,3-glucan synthesis inhibitor.
Year : 2021
Volume : 32
First Page : 127661
Last Page : 127661
Authors : Apgar JM,Wilkening RR,Parker DL,Meng D,Wildonger KJ,Sperbeck D,Greenlee ML,Balkovec JM,Flattery AM,Abruzzo GK,Galgoci AM,Giacobbe RA,Gill CJ,Hsu MJ,Liberator P,Misura AS,Motyl M,Nielsen Kahn J,Powles M,Racine F,Dragovic J,Fan W,Kirwan R,Lee S,Liu H,Mamai A,Nelson K,Peel M
Abstract : We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.
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Inhibition of Cryptococcus neoformans (H99) 1,3-beta-glucan synthase component FKS1 using UDP-[14C]glucose as substrate
|
Cryptococcus neoformans var. grubii H99
|
170.0
nM
|
|
Journal : J Med Chem
Title : Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12429
Last Page : 12459
Authors : Liu W,Yuan L,Wang S
Abstract : Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.
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Inhibition of Beta-1,3-glucan synthase in wild type Schizosaccharomyces pombe
|
Schizosaccharomyces pombe
|
0.3
ug.mL-1
|
|
Journal : J Med Chem
Title : Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12429
Last Page : 12459
Authors : Liu W,Yuan L,Wang S
Abstract : Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.
|
Inhibition of Beta-1,3-glucan synthase in Schizosaccharomyces pombe pbr1-8
|
Schizosaccharomyces pombe
|
250.0
ug.mL-1
|
|
Journal : J Med Chem
Title : Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12429
Last Page : 12459
Authors : Liu W,Yuan L,Wang S
Abstract : Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.
|
Inhibition of Beta-1,3-glucan synthase in Schizosaccharomyces pombe pbr1-6
|
Schizosaccharomyces pombe
|
150.0
ug.mL-1
|
|
Journal : J Med Chem
Title : Recent Progress in the Discovery of Antifungal Agents Targeting the Cell Wall.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12429
Last Page : 12459
Authors : Liu W,Yuan L,Wang S
Abstract : Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.
