Theoretical studies on beta-lactam antibiotics. I. Conformational similarity of penicillins and cephalosporins to X-D-alanyl-D-alanine and correlation of their structure with activity

Abstract

The substrate analogue hypothesis proposed for the mechanism of the action of penicillins and cephalosporins is examined by stereochemical criteria. These beta-lactam antibiotics assume conformation similar to X-D-alanyl-D-alanine due to the presence of the lactam ring; this disagrees with the assumption made by Tipper & Strominger that L and D amino acid residues take similar conformation. The model proposed in this study for the activity of these antibiotics differs considerably from the earlier models, mainly in phi2 rotational angle which determines the conformation of the aminoacyl group. The inactivity of C6 or C7 epimers and the effect of various substitutions at 6alpha or 7alpha and C2 positions of penicillins and cephalosporins on the biological activity are explained.