Inhibition of beta-lactamases by 6,6-bis(hydroxylmethyl)penicillanate.
beta-Lactamases of classes A and C are the two most prevalent resistant determinants to beta-lactam antibiotics among bacterial pathogens. Both these enzymes pursue different mechanisms for their catalytic processes, highlighted by the fact that the hydrolytic water molecule in each approaches the ester of the intermediary acyl-enzyme species from the opposite ends. 6,6-Bis(hydroxylmethyl)penicillanate was designed as an inhibitor that would impair the approach of the hydrolytic water molecule in either of these enzymes upon formation of the acyl-enzyme species. The design, synthesis, and kinetic evaluation of this inhibitor are disclosed herein.
Nagase
T
T
Department of Chemistry, Institute for Drug Design, Detroit, Michigan 48202-3489, USA.
Golemi
D
D
Ishiwata
A
A
Mobashery
S
S
D016972:Enterobacter cloacae / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D065093:beta-Lactamase Inhibitors
C445707:6,6-bis(hydroxylmethyl)penicillanate; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid