Effect of the 3′-leaving group on turnover of cephem antibiotics by a class C β-lactamase

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Abstract
It has been previously demonstrated for class A .beta.-lactamases and the DD-peptidase of Streptomyces R61 that the presence of a leaving group at the 3''-position of a cephalosporin can lead to the generation of more-inert acyl-enzyme intermediates than from cephalosporins lacking such a leaving group, and thus to .beta.-lactamase inhibitors and potentially better antibiotics. In the present work we extend this result to a class C .beta.-lactamase, that of Enterobacter cloacae P99. The effect is not seen with first-generation cephalosporins, since here deacylation generally seems faster than elimination of the leaving group, but it does clearly appear with cephamycins and third-generation cephalosporins. The structural and/or mechanistic features of the active site giving rise to this phenomenon may thus be common to all serine .beta.-lactamases and transpeptidases.

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