Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain.
J Med Chem. 2020 Mar 12;63(5):1859-1881. doi: 10.1021/acs.jmedchem.9b01279. Epub 2019 Nov 13.
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.
目前，由耐药菌引起的感染太过常见，一些病原体甚至对多种类型的抗生素都具有耐药性，在这种情况下，可用的治疗方法很少甚至没有。近年来，用于治疗此类棘手感染的抗感染药物发现中最成功的策略是联合治疗“抗生素+耐药抑制剂”。这些抑制剂可以重新利用已经证明对临床使用安全有效的抗生素。已经开发出三种主要类型的化合物来阻断主要的细菌耐药机制：（i）β-内酰胺酶抑制剂；（ii）外膜通透性增强剂；（iii）外排泵抑制剂。本观点主要关注β-内酰胺酶抑制剂，这些抑制剂可以使革兰氏阴性菌中最常见的抗生素耐药原因失活，即通过产生β-内酰胺酶使最广泛使用的抗生素（青霉素类、头孢菌素类、碳青霉烯类和单环β-内酰胺类）失活。本文概述了最近发现的β-内酰胺酶抑制剂和联合治疗方法。文章还涵盖了不同类型β-内酰胺酶的作用机制，作为抑制剂设计和靶标失活的基础。
