Conformation of peptidoglycan and mode of penicillin action

Abstract

Penicillins and cephalosporins are conformationally similar to D-L-Ala-D-Ala due to the presence of the lactam ring.

The mode of binding of the aminoacyl group of penicillin and cephalosporin with transpeptidase is the same, while that of the carboxyl group seems to be different.

The C6 or C7 epimers of penicillins and cephalosporins are completely inactive, since they cannot assume the required conformation to bind with transpeptidase. The 6? or 7? derivatives and the ?-sulfoxide derivative are less active because of the influence of these groups on the required conformation of the aminoacyl group.

To bind with the enzyme, the substrate X-D-Ala-D-Ala should assume conformations around ? ~ 180°, ? ~ -125°, ? ~ 160° and ? ~ 5°. Compared to penicillin, the above conformation is energetically less favoured for the substrate, and this explains the competitive inhibitory property of the antibiotic.