Beta-lactamases: a survey of protein diversity.
Bacterial resistance to beta-lactam antibiotics and beta-lactamase inhibitors is an ever increasing problem that threatens the clinical utility of drugs that form the cornerstone of the antibiotic armamentarium. Especially among Gram-negative pathogens, elaboration of structurally and mechanistically novel beta-lactamase enzymes is the most important means by which resistance occurs. An appreciation of the tremendous diversity of these drug-modifying enzymes will assist in understanding why so few generally effective inhibitory agents exist for these unique drug targets. This review will give a general background on the reaction mechanisms and classification schemes of the more than 340 beta-lactamase enzymes described to date. A discussion will follow highlighting the emerging Class A SHV and TEM-derived extended-spectrum (ESBLs), and inhibitor-resistant enzymes, non-TEM, non-SHV Class A ESBLs, and carbapenemases, Class B metallo-beta-lactamases and some of their novel inhibitors, plasmid and chromosomally encoded Class C enzymes, and finally, the OXA-type oxacillinases, ESBLs, and carbapenemases of Class D. The clinical importance of multiple resistance mechanisms in conjunction with the production of beta-lactamase enzymes is emphasized.
Helfand
Marion S
MS
Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, OH 44106, USA.
Bonomo
Robert A
RA
D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification
D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases