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

• Published in: FEMS microbiology reviews Vol. 24; no. 3; pp. 251 - 262
• Main Authors: Therrien, Christian, Levesque, Roger C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier B.V 01.07.2000; Blackwell
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; b-Lactam antibiotics; Bacteriology; beta-Lactam Resistance - genetics; beta-Lactamase Inhibitors; beta-Lactamases - chemistry; beta-Lactamases - genetics; beta-Lactamases - metabolism; beta-Lactams; Biological and medical sciences; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gram-Negative Bacteria - drug effects; Gram-Negative Bacterial Infections - microbiology; Humans; Metabolism. Enzymes; Microbiology; β-Lactam; β-Lactamase; Antibiotic resistance; β-Lactam; β-Lactamase; Resistance; Antibiotic; Enzyme; Hydrolases; Bacteria; Review; Inhibition; Antibacterial agent; Inactivation; Mechanism
• ISSN: 0168-6445; 1574-6976
• DOI: 10.1016/S0168-6445(99)00039-X

Antibacterial chemotherapy is particularly striking in the family of penicillins and cephalosporins. Over 40 structurally different β-lactam molecules are available in 73 formulations and the majority of them are currently prescribed for medical use in hospitals. β-Lactams are well tolerated by humans with few side effects. They interact very specifically with their bacterial target, the D-alanyl- D-alanine carboxypeptidase-transpeptidase usually referred to as DD-peptidase. The outstanding number of β-lactamases produced by bacteria represent a serious threat to the clinical utility of β-lactams. The discovery of β-lactamase inhibitors was thought to solve, in part, the problem of resistance. Unfortunately, bacteria have evolved new mechanisms of resistance to overcome the inhibitory effects of β-lactamase inactivators. Here, we summarize the diversified mechanistic features of class A β-lactamases interactions with mechanism-based inhibitors using available microbiological, kinetic and structural data for the prototype TEM β-lactamases. A brief historical overview of the strategies developed to counteract β-lactamases will be presented followed by a short description of the chemical events which lead to the inactivation of TEM β-lactamase by inhibitors from different classes. Finally, an update on the clinical prevalence of natural and inhibitor-resistant enzyme mutants, the total chemical synthesis to design and synthesize a new structure and produced a broad spectrum β-lactamase inhibitor that mimics the β-lactam ring, but does not contain it is discussed.