|
Inhibition of Escherichia coli beta-lactamase ACC4
|
Escherichia coli
|
32.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Plasmid-encoded ACC-4, an extended-spectrum cephalosporinase variant from Escherichia coli.
Year : 2007
Volume : 51
Issue : 10
First Page : 3763
Last Page : 3767
Authors : Papagiannitsis CC, Tzouvelekis LS, Tzelepi E, Miriagou V.
Abstract : ACC-4, an omega loop mutant (Val(211)-->Gly) of the Hafnia alvei-derived cephalosporinase ACC-1, was encoded by an Escherichia coli plasmid. The genetic environment of bla(ACC-4) shared similarities with plasmidic regions carrying bla(ACC-1). Kinetics of beta-lactam hydrolysis and levels of resistance to beta-lactams showed that ACC-4 was more effective than ACC-1 against expanded-spectrum cephalosporins.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 1b
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 1a
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 6
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 5
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 4
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 3
|
Escherichia coli
|
0.03
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 2
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 1b
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Escherichia coli MC4100 penicillin-binding protein 1a
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 2
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 3
|
Pseudomonas aeruginosa PAO1
|
0.03
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 4
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of bocillin FL binding to Pseudomonas aeruginosa PAO1 penicillin-binding protein 5/6
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Binding of ceftobiprole and comparators to the penicillin-binding proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae.
Year : 2007
Volume : 51
Issue : 7
First Page : 2621
Last Page : 2624
Authors : Davies TA, Page MG, Shang W, Andrew T, Kania M, Bush K.
Abstract : Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.
|
Inhibition of protein synthesis in Pseudomonas aeruginosa ATCC 27853 assessed as decrease in incorporation of L-[4,5-3H]leucine at 10 times MIC by liquid scintillation counter relative to control
|
Pseudomonas aeruginosa
|
95.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimicrobial evaluation of amphiphilic neamine derivatives.
Year : 2010
Volume : 53
Issue : 1
First Page : 119
Last Page : 127
Authors : Baussanne I, Bussière A, Halder S, Ganem-Elbaz C, Ouberai M, Riou M, Paris JM, Ennifar E, Mingeot-Leclercq MP, Décout JL.
Abstract : The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4'- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, as compared to neomycin B, 10a showed a lower ability to decrease (3)H leucine incorporation into proteins in Pseudomonas aeruginosa. All together, our results suggest that the 3',4',6-tri-2-naphthylmethylene neamine derivative 10a should act against Gram (-) bacteria through a mechanism different from inhibition of protein synthesis, probably by membrane destabilization.
|
Inhibition of protein synthesis in Pseudomonas aeruginosa ATCC 27853 assessed as decrease in incorporation of L-[4,5-3H]leucine at 5 times MIC by liquid scintillation counter relative to control
|
Pseudomonas aeruginosa
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antimicrobial evaluation of amphiphilic neamine derivatives.
Year : 2010
Volume : 53
Issue : 1
First Page : 119
Last Page : 127
Authors : Baussanne I, Bussière A, Halder S, Ganem-Elbaz C, Ouberai M, Riou M, Paris JM, Ennifar E, Mingeot-Leclercq MP, Décout JL.
Abstract : The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4'- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, as compared to neomycin B, 10a showed a lower ability to decrease (3)H leucine incorporation into proteins in Pseudomonas aeruginosa. All together, our results suggest that the 3',4',6-tri-2-naphthylmethylene neamine derivative 10a should act against Gram (-) bacteria through a mechanism different from inhibition of protein synthesis, probably by membrane destabilization.
|
Inhibition of Escherichia coli ATCC 25922 AmpC
|
Escherichia coli
|
60.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli.
Year : 2010
Volume : 54
Issue : 6
First Page : 2291
Last Page : 2302
Authors : Page MG, Dantier C, Desarbre E.
Abstract : BAL30072 is a new monocyclic beta-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with beta-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC(90)s were 4 microg/ml for MDR Acinetobacter spp. and 8 microg/ml for MDR P. aeruginosa, whereas the MIC(90) of meropenem for the same sets of isolates was >32 microg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-beta-lactamases that conferred resistance to all other beta-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-beta-lactamase. Unlike other monocyclic beta-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.
|
Inhibition of Escherichia coli Penicillin-binding protein 3
|
Escherichia coli
|
23.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant gram-negative bacilli.
Year : 2010
Volume : 54
Issue : 6
First Page : 2291
Last Page : 2302
Authors : Page MG, Dantier C, Desarbre E.
Abstract : BAL30072 is a new monocyclic beta-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with beta-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC(90)s were 4 microg/ml for MDR Acinetobacter spp. and 8 microg/ml for MDR P. aeruginosa, whereas the MIC(90) of meropenem for the same sets of isolates was >32 microg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-beta-lactamases that conferred resistance to all other beta-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-beta-lactamase. Unlike other monocyclic beta-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.
|
Inhibition of Bocillin FL binding to PBP1A in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP1B in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP2 in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP3 in Escherichia coli MC4100 membranes
|
Escherichia coli
|
0.03
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP4 in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP5 in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP6 in Escherichia coli MC4100 membranes
|
Escherichia coli
|
8.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP1A in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP1B in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP2 in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP3 in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
0.03
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP4 in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP5/6 in Pseudomonas aeruginosa PAO1 membranes
|
Pseudomonas aeruginosa PAO1
|
16.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP1A in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP1B in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
2.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP2 in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
4.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP3 in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
0.02
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP4 in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
4.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Inhibition of Bocillin FL binding to PBP5/6 in Pseudomonas aeruginosa 27853 membranes
|
Pseudomonas aeruginosa PAO1
|
4.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Affinity of doripenem and comparators to penicillin-binding proteins in Escherichia coli and Pseudomonas aeruginosa.
Year : 2008
Volume : 52
Issue : 4
First Page : 1510
Last Page : 1512
Authors : Davies TA, Shang W, Bush K, Flamm RK.
Abstract : Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectrum gram-negative activity observed with doripenem.
|
Activity of Enterobacter cloacae P99 beta-lactamase
|
Enterobacter cloacae
|
1.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Updated functional classification of beta-lactamases.
Year : 2010
Volume : 54
Issue : 3
First Page : 969
Last Page : 976
Authors : Bush K, Jacoby GA.
Abstract : Two classification schemes for beta-lactamases are currently in use. The molecular classification is based on the amino acid sequence and divides beta-lactamases into class A, C, and D enzymes which utilize serine for beta-lactam hydrolysis and class B metalloenzymes which require divalent zinc ions for substrate hydrolysis. The functional classification scheme updated herein is based on the 1995 proposal by Bush et al. (K. Bush, G. A. Jacoby, and A. A. Medeiros, Antimicrob. Agents Chemother. 39:1211-1233, 1995). It takes into account substrate and inhibitor profiles in an attempt to group the enzymes in ways that can be correlated with their phenotype in clinical isolates. Major groupings generally correlate with the more broadly based molecular classification. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, and extended-spectrum beta-lactamases and serine carbapenemases; and group 3 metallo-beta-lactamases. Several new subgroups of each of the major groups are described, based on specific attributes of individual enzymes. A list of attributes is also suggested for the description of a new beta-lactamase, including the requisite microbiological properties, substrate and inhibitor profiles, and molecular sequence data that provide an adequate characterization for a new beta-lactam-hydrolyzing enzyme.
|
Inhibition of Salmonella enterica serotype Newport AM17274 cephalosporinase CMY-31 by UV spectrophotometer in presence of 100 uM of cephalothin
|
Salmonella enterica subsp. enterica serovar Newport
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : CMY-31 and CMY-36 cephalosporinases encoded by ColE1-like plasmids.
Year : 2009
Volume : 53
Issue : 3
First Page : 1256
Last Page : 1259
Authors : Zioga A, Whichard JM, Kotsakis SD, Tzouvelekis LS, Tzelepi E, Miriagou V.
Abstract : Two CMY-2 derivatives, CMY-31 (Gln(215)-->Arg) from Salmonella enterica serotype Newport and CMY-36 (Ala(77)-->Cys and Gln(193)-->Glu) from Klebsiella pneumoniae, were characterized. Both cephalosporinases functionally resembled CMY-2. bla(CMY) alleles occurred as parts of a putative transposon comprising ISEcp1B and a Citrobacter freundii-derived sequence carried by ColE1-like plasmids similar to CMY-5-encoding pTKH11 from Klebsiella oxytoca.
|
Inhibition of Klebsiella pneumoniae HP205 cephalosporinase CMY-36 by UV spectrophotometer in presence of 100 uM of cephalothin
|
Klebsiella pneumoniae
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : CMY-31 and CMY-36 cephalosporinases encoded by ColE1-like plasmids.
Year : 2009
Volume : 53
Issue : 3
First Page : 1256
Last Page : 1259
Authors : Zioga A, Whichard JM, Kotsakis SD, Tzouvelekis LS, Tzelepi E, Miriagou V.
Abstract : Two CMY-2 derivatives, CMY-31 (Gln(215)-->Arg) from Salmonella enterica serotype Newport and CMY-36 (Ala(77)-->Cys and Gln(193)-->Glu) from Klebsiella pneumoniae, were characterized. Both cephalosporinases functionally resembled CMY-2. bla(CMY) alleles occurred as parts of a putative transposon comprising ISEcp1B and a Citrobacter freundii-derived sequence carried by ColE1-like plasmids similar to CMY-5-encoding pTKH11 from Klebsiella oxytoca.
|
Inhibition of CMY-2 by UV spectrophotometer in presence of 100 uM of cephalothin
|
None
|
6.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : CMY-31 and CMY-36 cephalosporinases encoded by ColE1-like plasmids.
Year : 2009
Volume : 53
Issue : 3
First Page : 1256
Last Page : 1259
Authors : Zioga A, Whichard JM, Kotsakis SD, Tzouvelekis LS, Tzelepi E, Miriagou V.
Abstract : Two CMY-2 derivatives, CMY-31 (Gln(215)-->Arg) from Salmonella enterica serotype Newport and CMY-36 (Ala(77)-->Cys and Gln(193)-->Glu) from Klebsiella pneumoniae, were characterized. Both cephalosporinases functionally resembled CMY-2. bla(CMY) alleles occurred as parts of a putative transposon comprising ISEcp1B and a Citrobacter freundii-derived sequence carried by ColE1-like plasmids similar to CMY-5-encoding pTKH11 from Klebsiella oxytoca.
|
Inhibition of Escherichia coli MC4100 Beta-Lactamase CMY-30 using cephalothin as reporter substrate
|
Escherichia coli
|
17.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Extended-spectrum properties of CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase.
Year : 2009
Volume : 53
Issue : 8
First Page : 3520
Last Page : 3523
Authors : Kotsakis SD, Papagiannitsis CC, Tzelepi E, Tzouvelekis LS, Miriagou V.
Abstract : CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase, was derived by mutagenesis. The hydrolytic efficiency of CMY-30 against expanded-spectrum cephalosporins was higher than that of CMY-2 due to increased k(cat) values. Findings indicate a role of the Omega loop residue 211 in determining the substrate specificities of CMYs also corroborated by modeling studies.
|
Inhibition of Escherichia coli MC4100 Beta-Lactamase CMY-2 using cephalothin as reporter substrate
|
Escherichia coli
|
2.1
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Extended-spectrum properties of CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase.
Year : 2009
Volume : 53
Issue : 8
First Page : 3520
Last Page : 3523
Authors : Kotsakis SD, Papagiannitsis CC, Tzelepi E, Tzouvelekis LS, Miriagou V.
Abstract : CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase, was derived by mutagenesis. The hydrolytic efficiency of CMY-30 against expanded-spectrum cephalosporins was higher than that of CMY-2 due to increased k(cat) values. Findings indicate a role of the Omega loop residue 211 in determining the substrate specificities of CMYs also corroborated by modeling studies.
|
Activity of Acinetobacter baumannii ADC-33 beta-lactamase
|
Acinetobacter baumannii
|
7.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Extended-spectrum cephalosporinase in Acinetobacter baumannii.
Year : 2010
Volume : 54
Issue : 8
First Page : 3484
Last Page : 3488
Authors : Rodríguez-Martínez JM, Nordmann P, Ronco E, Poirel L.
Abstract : An AmpC-type beta-lactamase conferring high-level resistance to expanded-spectrum cephalosporins and monobactams was characterized from an Acinetobacter baumannii clinical isolate. This class C beta-lactamase (named ADC-33) possessed a Pro210Arg substitution together with a duplication of an Ala residue at position 215 (inside the Omega-loop) compared to a reference AmpC cephalosporinase from A. baumannii. ADC-33 hydrolyzed ceftazidime, cefepime, and aztreonam at high levels, which allows the classification of this enzyme as an extended-spectrum AmpC (ESAC). Site-directed mutagenesis confirmed the role of both substitutions in its ESAC property.
|
Inhibition of PBP3 in Pseudomonas aeruginosa ATCC 27853 after 20 mins by fluorescence assay
|
Pseudomonas aeruginosa
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Pyridone-conjugated monobactam antibiotics with gram-negative activity.
Year : 2013
Volume : 56
Issue : 13
First Page : 5541
Last Page : 5552
Authors : Brown MF, Mitton-Fry MJ, Arcari JT, Barham R, Casavant J, Gerstenberger BS, Han S, Hardink JR, Harris TM, Hoang T, Huband MD, Lall MS, Lemmon MM, Li C, Lin J, McCurdy SP, McElroy E, McPherson C, Marr ES, Mueller JP, Mullins L, Nikitenko AA, Noe MC, Penzien J, Plummer MS, Schuff BP, Shanmugasundaram V, Starr JT, Sun J, Tomaras A, Young JA, Zaniewski RP.
Abstract : Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
|
Displacement of fluorescent Bocillin FL from Pseudomonas aeruginosa PBP3
|
Pseudomonas aeruginosa
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Siderophore receptor-mediated uptake of lactivicin analogues in gram-negative bacteria.
Year : 2014
Volume : 57
Issue : 9
First Page : 3845
Last Page : 3855
Authors : Starr J, Brown MF, Aschenbrenner L, Caspers N, Che Y, Gerstenberger BS, Huband M, Knafels JD, Lemmon MM, Li C, McCurdy SP, McElroy E, Rauckhorst MR, Tomaras AP, Young JA, Zaniewski RP, Shanmugasundaram V, Han S.
Abstract : Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.89
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.61
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
7.203
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.06
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
