|
In vitro inhibition of glucan synthase obtained from Candida albicans at a concentration of 10 ug/mL.
|
Candida albicans
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB.
Year : 1995
Volume : 38
Issue : 17
First Page : 3271
Last Page : 3281
Authors : Debono M, Turner WW, LaGrandeur L, Burkhardt FJ, Nissen JS, Nichols KK, Rodriguez MJ, Zweifel MJ, Zeckner DJ, Gordee RS.
Abstract : Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.
|
Antifungal activity against Candida glabrata 05-761 isolate in presence of 5% human serum after 24 hrs by broth microdilution method
|
Candida glabrata
|
0.31
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
|
1.7
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
|
0.05
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
|
0.31
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
|
1.7
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
|
0.001003
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
|
0.004715
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
|
0.01875
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
|
0.02937
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
|
0.00075
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
|
0.0019
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
|
0.0031
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
|
0.0119
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
|
0.00029
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
|
0.0055
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
|
0.0069
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
|
0.0281
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
|
0.0133
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
|
0.0214
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
|
0.0774
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
|
0.001
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 Candida albicans ATCC 90028 in presence of 10% human serum
|
Candida albicans
|
0.00472
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
|
0.0186
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
|
0.0247
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
|
0.0185
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
|
0.024
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
|
0.0715
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
|
0.0171
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
|
0.0153
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
|
0.0747
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
|
0.089
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 wild-type 1,3-beta-D-glucan synthase KU80delta from Aspergillus fumigatus assessed as incorporation of [3H]glucose
|
Aspergillus fumigatus
|
0.00024
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
|
0.02917
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
|
0.00037
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.
|
Antifungal activity against Candida albicans GDH2346 grown as biofilm assessed as maximum inhibition of biofilm metabolic activity at 8 mg/liter after 24 hrs by XTT assay relative to control
|
Candida albicans
|
40.0
%
|
|
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 M61 grown as biofilm assessed as maximum inhibition of biofilm metabolic activity at 0.5 mg/liter after 24 hrs by XTT assay relative to control
|
Candida albicans
|
40.0
%
|
|
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).
|
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
|
|
Inhibition of Candida glabrata ATCC 90030 wild type FKS
|
Candida glabrata
|
3.189
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.
|
Inhibition of Candida glabrata CG-C2 wild type FKS
|
Candida glabrata
|
14.26
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 wild type FKS
|
Candida glabrata
|
13.29
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 parapsilosis ATCC 22019 glucan synthase by assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.442
ug.mL-1
|
|
Inhibition of Candida parapsilosis ATCC 22019 glucan synthase by assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
639.5
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.
|
Inhibition of Candida parapsilosis H4 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.1101
ug.mL-1
|
|
Inhibition of Candida parapsilosis H4 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
368.5
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.
|
Inhibition of Candida parapsilosis H5 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
0.2371
ug.mL-1
|
|
Inhibition of Candida parapsilosis H5 glucan synthase assessed as [3H]UDPG incorporation
|
Candida parapsilosis
|
431.67
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 orthopsilosis H10 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
0.1632
ug.mL-1
|
|
Inhibition of Candida orthopsilosis H10 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
111.0
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
|
0.1419
ug.mL-1
|
|
Inhibition of Candida orthopsilosis 981224 glucan synthase assessed as [3H]UDPG incorporation
|
Candida orthopsilosis
|
46.5
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.
|
Inhibition of Candida metapsilosis am-2006-0113 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
0.1264
ug.mL-1
|
|
Inhibition of Candida metapsilosis am-2006-0113 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
41.4
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 960161 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
0.1333
ug.mL-1
|
|
Inhibition of Candida metapsilosis 960161 glucan synthase assessed as [3H]UDPG incorporation
|
Candida metapsilosis
|
129.0
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
|
0.1074
ug.mL-1
|
|
Inhibition of Saccharomyces cerevisiae BY4742 glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
68.95
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 Saccharomyces cerevisiae BY4742-FKS1P649A mutant glucan synthase assessed as [3H]UDPG incorporation
|
Saccharomyces cerevisiae
|
1.663
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
|
1.33
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
|
0.00089
ug.mL-1
|
|
Inhibition of Candida albicans Sc5314 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
1.43
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
|
0.00163
ug.mL-1
|
|
Inhibition of Candida albicans ATCC 90028 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
0.63
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
|
0.00183
ug.mL-1
|
|
Inhibition of Candida albicans ATCC 36082 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
646.07
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
|
0.5301
ug.mL-1
|
|
Inhibition of Candida albicans M122 glucan synthase assessed as [3H]UDPG incorporation
|
Candida albicans
|
16.15
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
|
0.00377
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
|
0.2069
ug.mL-1
|
|
Inhibition of Candida glabrata T51916 glucan synthase assessed as [3H]UDPG incorporation
|
Candida glabrata
|
712.0
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 tropicalis ATCC 750 glucan synthase subunit FKS1p at monophasic kinetics
|
Candida tropicalis
|
0.004661
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
|
0.002689
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
|
0.00032
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
|
0.2332
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
|
0.000574
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
|
0.4075
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
|
0.03162
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
|
0.00183
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
|
0.989
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
|
1.33
ng/ml
|
|
Inhibition of Candida albicans SC5314 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans SC5314
|
0.00089
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 36082 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
1.43
ng/ml
|
|
Inhibition of Candida albicans 36082 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00151
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 90028 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.63
ng/ml
|
|
Inhibition of Candida albicans 90028 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00183
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 1002 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
2.39
ng/ml
|
|
Inhibition of Candida albicans 1002 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00796
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 3107 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
1.67
ng/ml
|
|
Inhibition of Candida albicans 3107 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00312
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 3795 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
16.7
ng/ml
|
|
Inhibition of Candida albicans 3795 1,3-beta-D-glucan synthase subunit FKS1p
|
Candida albicans
|
0.00676
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 119 1,3-beta-D-glucan synthase subunit FKS1p T1921C mutant
|
Candida albicans
|
6.77
ng/ml
|
|
Inhibition of Candida albicans 119 1,3-beta-D-glucan synthase subunit FKS1p T1921C mutant
|
Candida albicans
|
0.0113
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 177 1,3-beta-D-glucan synthase subunit FKS1p T1922C mutant
|
Candida albicans
|
2.622
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
|
1.085
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 205 1,3-beta-D-glucan synthase subunit FKS1p T1933C mutant
|
Candida albicans
|
0.989
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
|
1.152
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
|
2.739
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 85 1,3-beta-D-glucan synthase subunit FKS1p C1934T mutant
|
Candida albicans
|
445.93
ng/ml
|
|
Inhibition of Candida albicans 85 1,3-beta-D-glucan synthase subunit FKS1p C1934T mutant
|
Candida albicans
|
0.787
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 149 1,3-beta-D-glucan synthase subunit FKS1p G1942T mutant
|
Candida albicans
|
170.55
ng/ml
|
|
Inhibition of Candida albicans 149 1,3-beta-D-glucan synthase subunit FKS1p G1942T mutant
|
Candida albicans
|
0.0933
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 122 1,3-beta-D-glucan synthase subunit FKS1p C1946A mutant
|
Candida albicans
|
646.07
ng/ml
|
|
Inhibition of Candida albicans 122 1,3-beta-D-glucan synthase subunit FKS1p C1946A mutant
|
Candida albicans
|
0.491
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 121 1,3-beta-D-glucan synthase subunit FKS1p G4082A mutant
|
Candida albicans
|
84.57
ng/ml
|
|
Inhibition of Candida albicans 121 1,3-beta-D-glucan synthase subunit FKS1p G4082A mutant
|
Candida albicans
|
0.07599
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 194 1,3-beta-D-glucan synthase subunit FKS1p C1934T/G4082R mutant
|
Candida albicans
|
299.24
ng/ml
|
|
Inhibition of Candida albicans 194 1,3-beta-D-glucan synthase subunit FKS1p C1934T/G4082R mutant
|
Candida albicans
|
0.782
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 90 1,3-beta-D-glucan synthase subunit FKS1p G4082R mutant
|
Candida albicans
|
48.5
ng/ml
|
|
Inhibition of Candida albicans 90 1,3-beta-D-glucan synthase subunit FKS1p G4082R mutant
|
Candida albicans
|
0.0406
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 1,3-beta-D-glucan synthase subunit FKS1p T1933Y mutant
|
Candida albicans
|
0.1287
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
|
0.901
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 human CYP2C8 at 17.5 uM in presence of rosiglitazone
|
Homo sapiens
|
34.3
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin.
Year : 2009
Volume : 53
Issue : 3
First Page : 1149
Last Page : 1156
Authors : Damle BD, Dowell JA, Walsky RL, Weber GL, Stogniew M, Inskeep PB.
Abstract : Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.
|
Inhibition of Candida albicans isolate 1 adherence to human buccal epithelial cells at 4 times MIC after 1 hr by adherence assay relative to control
|
Candida albicans
|
58.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Inhibition of Candida parapsilosis isolate A adherence to human buccal epithelial cells at 4 times MIC after 1 hr by adherence assay relative to control
|
Candida parapsilosis
|
69.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Inhibition of Candida glabrata isolate 1 adherence to human buccal epithelial cells at 4 times MIC after 1 hr by adherence assay relative to control
|
Candida glabrata
|
62.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Antifungal activity against Candida albicans isolate 1 coincubated with mouse J774 macrophages assessed as macrophage induced bacterial cell killing at 4 times MIC (Rvb = 14 +/- 8 %)
|
Candida albicans
|
37.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Antifungal activity against Candida parapsilosis isolate A coincubated with mouse J774 macrophages assessed as macrophage induced bacterial cell killing at 4 times MIC (Rvb = 19 +/- 9 %)
|
Candida parapsilosis
|
42.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Antifungal activity against Candida parapsilosis isolate 1 coincubated with mouse J774 macrophages assessed as macrophage induced bacterial cell killing at 4 times MIC (Rvb = 22 +/- 12 %)
|
Candida parapsilosis
|
27.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Antifungal activity against Candida glabrata isolate 1 coincubated with mouse J774 macrophages assessed as macrophage induced bacterial cell killing at 4 times MIC (Rvb = 12 +/- 10 %)
|
Candida glabrata
|
33.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Anidulafungin is fungicidal and exerts a variety of postantifungal effects against Candida albicans, C. glabrata, C. parapsilosis, and C. krusei isolates.
Year : 2009
Volume : 53
Issue : 8
First Page : 3347
Last Page : 3352
Authors : Nguyen KT, Ta P, Hoang BT, Cheng S, Hao B, Nguyen MH, Clancy CJ.
Abstract : Anidulafungin targets the cell walls of Candida species by inhibiting beta-1,3-glucan synthase, thereby killing isolates and exerting prolonged postantifungal effects (PAFEs). We performed time-kill and PAFE experiments on Candida albicans (n = 4), C. glabrata (n = 3), C. parapsilosis (n = 3), and C. krusei (n = 2) isolates and characterized the PAFEs in greater detail. MICs were 0.008 to 0.125 microg/ml against C. albicans, C. glabrata, and C. krusei and 1.0 to 2.0 microg/ml against C. parapsilosis. During time-kill experiments, anidulafungin caused significant kills at 16x MIC (range, log 2.68 to 3.89) and 4x MIC (log 1.87 to 3.19), achieving fungicidal levels (>or=log 3) against nine isolates. A 1-hour drug exposure during PAFE experiments resulted in kills ranging from log 1.55 to 3.47 and log 1.18 to 2.89 (16x and 4x MIC, respectively), achieving fungicidal levels against four isolates. Regrowth of all 12 isolates was inhibited for >or=12 h after drug washout. Isolates of each species collected 8 h after a 1-hour exposure to anidulafungin (16x and 4x MIC) were hypersusceptible to sodium dodecyl sulfate (0.01 to 0.04%) and calcofluor white (40 microg/ml). Moreover, PAFEs were associated with major cell wall disturbances, as evident in electron micrographs of viable cells, and significant reductions in adherence to buccal epithelial cells (P <or= 0.01). Finally, three of four PAFE isolates tested were hypersusceptible to killing by J774 macrophages (P <or= 0.007). Our data suggest that the efficacy of anidulafungin in the treatment of candidiasis might stem from both direct fungicidal activity and indirect PAFEs that lessen the ability of Candida cells to establish invasive disease and to persist within infected hosts.
|
Inhibition of Candida glabrata ATCC 90030 wild type 1,3-beta-D-glucan synthase
|
Candida glabrata
|
0.00191
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
|
0.00125
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
|
0.00158
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
|
0.1106
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
|
3.855
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
|
0.1018
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
|
0.1515
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
|
2.543
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
|
0.16
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
|
0.0866
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
|
0.8581
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
|
4.003
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
|
0.1758
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
|
0.1274
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
|
0.0995
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
|
0.0852
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.
