On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis.

Electrostatic and structural properties of a set of beta-lactam, gamma-lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate D-alanyl-D-alanine for the carboxy- and transpeptidase enzymes. This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics. The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k2/K) in accordance with the model for interaction of the lactam compounds with DD-peptidase. These correlations provide a better prediction of antibacterial activity than purely structural criteria.