Theoretical studies on β-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 β-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 φ₂ rotational angle which determines the conformation of the aminoacyl group. The inactivity of _C6 or C₇ epimers and the effect of various substitutions at 6α or 7α and C₂ positions of penicillins and cephalosporins on the biological activity are explained.