Substrate Inhibition of Beta-Lactamases, a Method for Predicting Enzymatic Stability of Cephalosporins
Open Access
- 1 September 1976
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 10 (3), 470-475
- https://doi.org/10.1128/aac.10.3.470
Abstract
Selected cephalosporins, including cefamandole, cephaloridine, cephaloglycin, and cefoxitin, were examined for their ability to inhibit the enzymatic activity of and act as substrates for beta-lactamases produced by Enterobacter cloacae and Staphylococcus aureus . Enzyme inhibition was determined by Michaelis-Menten kinetic measurements and by a spot plate assay using a chromogenic substrate (Glaxo compound 87/312). These two methods provide comparable estimates of kinetic parameters. Inhibition of beta-lactamase, as measured by these two methods, was generally found to correlate with resistance to hydrolysis and is proposed as a preliminary method of assessing susceptibility of cephalosporins to beta-lactamase hydrolysis. Four 7-αOCH 3 , 7-αH cephalosporin analogue pairs were also examined. The presence of the 7-αOCH 3 substituent invariably resulted in reduced susceptibility to enzymatic hydrolysis, regardless of the other C7 substituent. The 7-αOCH 3 compounds were also better inhibitors than were their 7-αH analogues, with the exception that 7-αOCH 3 compounds having C7 adipic acid substituents were less inhibitory to the S. aureus enzyme than were the corresponding 7-αH analogues. Response of these two enzymes to 7-αOCH 3 and 7-αH cephalosporins suggests that beta-lactamase hydrolysis of these compounds involves attack at the alpha side of the betalactam ring.Keywords
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