Conformational analysis of β and γ-lactam antibiotics

Geometry optimization, superimposition searches and conformational analysis carried on several lactam antibiotics show that reactivity with the active-site serine penicillin-binding proteins is related to a particular spatial disposition of 2 flanking functional groups - namely a C = O or C-OH on 1 side and a carboxylate on the other - with respect to the central scissile amide bond. Such a binding entity is found in one of the most stable conformers of the tripeptide diacetyl-L-Lys-D-Ala-D-Ala conferring substrate activity, and in benzylpenicillin, cephapyrin, thienamycin, gamma-lactam, the 6-spiro-epoxypenicillin S and in one epimer of lactivicin, conferring inactivating potency. This binding entity generates a particular electronic distribution and the fact that it is conserved in compounds belonging to very different chemical families strongly suggests that it is an important feature required for enzyme recognition.