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 t hose of a model of the natural substrate D-alanyl-D-alanine for the ca rboxy- and transpeptidase enzymes. This first comparison of the electr ostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potentia l antibiotics. The electrostatic similarity of the substrate and activ e compounds is apparent, and contrasts with the electrostatic properti es of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and w ith kinetic data (k(2)/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.