Beta-lactamase inhibitors: the story so far.
Antimicrobial resistance constitutes one of the major threats regarding pathogenic microorganisms. Gram-negative pathogens, such as Enterobacteriaceae (specially those producing extended-spectrum beta-lactamases), Pseudomonas aeruginosa, and Acinetobacter baumannii have acquired an important role in hospital infections, which is of particular concern because of the associated broad spectrum of antibiotic resistance. beta-Lactam antibiotics are considered the most successful antimicrobial agents since the beginning of the antibiotic era. Soon after the introduction of penicillin, microorganisms able to destroy this beta-lactam antibiotic were reported, thus emphasizing the facility of pathogenic microorganisms to develop beta-lactam resistance. In Gram-negative pathogens, beta-lactamase production is the main mechanism involved in acquired beta-lactam resistance. Four classes of beta-lactamases have been described: A, B, C, and D. Classes A, C, and D are enzymes with a serine moiety in the active centre that catalyzes hydrolysis of the beta -lactam ring through an acyl-intermediate of serine, whereas the class B enzymes require a metal cofactor (e.g. zinc in the natural form) to function, and for this reason, they are also referred to as metallo- beta-lactamases (MBLs). To overcome beta-lactamase-mediated resistance, a combination of beta-lactam and a beta-lactamase inhibitor, which protects the beta-lactam antibiotic from the activity of the beta-lactamase, has been widely used in the treatment of human infections. Although there are some very successful combinations of beta-lactams and beta-lactamase inhibitors, most of the inhibitors act against class A beta-lactamases and remain ineffective against class B, C, and D beta-lactamases. This review constitutes an update of the current status and knowledge regarding class A to D beta-lactamase inhibitors, as well as a summary of the drug discovery strategy currently used to identify new beta-lactamase inhibitors, mainly based on the knowledge of crystal structure of beta-lactamase enzymes.
Pérez-Llarena
Francisco J
FJ
Laboratorio de Microbiología, CH Universitario A Coruña-INIBIC, Xubias de Arriba s/n, A Coruña, Spain.
Bou
Germán
G
D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D015394:Molecular Structure; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000494:pharmacology
D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases