Molecular basis of antibiotic resistance and beta-lactamase inhibition by mechanism-based inactivators: perspectives and future directions

Antibacterial chemotherapy is particularly striking in the family of penici llins and cephalosporins. Over 40 structurally different beta-lactam molecu les are available in 73 formulations and the majority of them are currently prescribed for medical use in hospitals. beta-Lactams are well tolerated b y humans with few side effects. They interact very specifically with their bacterial target, the D-alanyl-D-alanine carboxypeptidase-transpeptidase us ually referred to as DD-peptidase. The outstanding number of beta-lactamase s produced by bacteria represent a serious threat to the clinical utility o f beta-lactams. The discovery of beta-lactamase inhibitors was thought to s olve,in part, the problem of resistance. Unfortunately, bacteria have evolv ed new mechanisms of resistance to overcome the inhibitory effects of beta- lactamase inactivators. Here, we summarize the diversified mechanistic feat ures of class A beta-lactamases interactions with mechanism-based inhibitor s using available microbiological, kinetic and structural data for the prot otype TEM beta-lactamases. A brief historical overview of the strategies de veloped to counteract beta-lactamases will be presented followed by a short description of the chemical events which lead to the inactivation of TEM b eta-lactamase by inhibitors from different classes. Finally, an update on t he clinical prevalence of natural and inhibitor-resistant enzyme mutants, t he total chemical synthesis to design and synthesize a new structure and pr oduced a broad spectrum beta-lactamase inhibitor that mimics the beta-lacta m ring, but does not contain it is discussed. (C) 2000 Federation of Europe an Microbiological Societies: Published by Elsevier Science B.V. All rights reserved.