Theoretical Studies on eta -lactam Antibiotics. IV. Conformational Analysis of Novel eta -lactam Antibiotics and the Binding Specificities of Crosslinking Enzyme(s) and eta -lactamases

摘要

Conformational-energy calculations were carried out on the new family of eta -lactam antibiotics (viz., thienamycin, PS-5, 1-oxa- and 1-thiapenems, and their close analogs); these exhibit broad-spectrum antibacterial activity and stability towards eta -lactamase-producing strains. The bicyclic ring system in all the compounds studied was found to be highly rigid and to favor only one conformation. This is in contrast to findings in penicillins, where the five-membered ring assumes two puckered conformations. The relative orientations of the bicyclic ring system and the nature and configuration of the substituent at C-5 position, besides nonplanarity of the lactam peptide bond, are shown to be important for biological activity. The present study, in agreement with x-ray studies, predicts that the lactam peptide bond in 1-carbapenem is more nonplanar than in 1-thiapenem. These studies also suggest that the conformational requirement of bicyclic ring system to bind to crosslinking enzyme(s) and eta -lactamases is very similar.