Theoretical studies on beta-lactam antibiotics. IV. Conformational analysis of novel beta-lactam antibiotics and the binding specificities of crosslinking enzyme (s) and beta-lactamases

Vasudevan, T.K.; Rao, V.S.

Biopolymers 20(5): 865-877

1981


ISSN/ISBN: 0006-3525
PMID: 6971662
DOI: 10.1002/bip.1981.360200502
Accession: 044790295

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Abstract
Conformational-energy calculations were carried out on the new family of .beta.-lactam antibiotics (i.e., thienamycin, PS-5, 1-oxa- and 1-thiapenems and their close analogs); these exhibit broad-spectrum antibacterial activity and stability towards .beta.-lactamase-producing strains. The bicyclic ring system in all the compounds studied was highly rigid and favors only 1 conformation. This is in contrast to findings in penicillins, where the 5-membered ring assumes 2 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 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 .beta.-lactamases is very similar.

Theoretical studies on beta-lactam antibiotics. IV. Conformational analysis of novel beta-lactam antibiotics and the binding specificities of crosslinking enzyme(s) and beta-lactamases