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González-Bello, Concepción; Rodríguez, Diana; Pernas, Marina; Rodríguez, Ángela; Colchón, Esther
Journal of medicinal chemistry, 03/2020, Volume: 63, Issue: 5Journal Article
Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy “antibiotic + inhibitor of resistance”. These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clinical use. Three main types of compounds have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; (iii) efflux pump inhibitors. This Perspective is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-negative bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems, and monobactams), by the production of β-lactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.
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