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Substrate Inhibition of Beta-Lactamases, a Method for Predicting Enzymatic Stability of Cephalosporins

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-αOCH3, 7-αH cephalosporin analogue pairs were also examined. The presence of the 7-αOCH3 substituent invariably resulted in reduced susceptibility to enzymatic hydrolysis, regardless of the other C7 substituent. The 7-αOCH3 compounds were also better inhibitors than were their 7-αH analogues, with the exception that 7-αOCH3 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-αOCH3 and 7-αH cephalosporins suggests that beta-lactamase hydrolysis of these compounds involves attack at the alpha side of the betalactam ring.