金属β-内酰胺酶抑制剂:对抗抗生素耐药性的持续挑战

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biophysical chemistry Pub Date : 2024-03-25 DOI:10.1016/j.bpc.2024.107228
Su-Jin Kang , Do-Hee Kim , Bong-Jin Lee
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引用次数: 0

摘要

β-内酰胺类抗生素是最成功、最常用的抗菌药物,但这些药物耐药性的出现已成为全球健康的威胁。病原体产生的β-内酰胺酶能水解β-内酰胺环的酰胺键,这种酶的表达是细菌对β-内酰胺类药物产生耐药性的主要机制。特别是在 A、B、C 和 D 类 β-内酰胺酶中,金属-β-内酰胺酶(MBLs,B 类 β-内酰胺酶)被认为是导致革兰氏阴性细菌产生耐药性的关键因素。为了消除β-内酰胺酶介导的耐药性,人们一直在努力开发能恢复β-内酰胺活性的β-内酰胺酶抑制剂。一些β-内酰胺酶抑制剂,如二氮杂双环辛烷(DBO)和硼酸衍生物,也已获得美国食品及药物管理局的批准。临床上使用的抑制剂主要能灭活丝氨酸-β-内酰胺酶(SBLs,A、C 和 D 类 β-内酰胺酶),但迄今为止还不能有效抑制 MBLs。为了开发特别针对 MBLs 的新抑制剂,人们进行了各种尝试。根据对 MBL 酶的结构和机理研究,近年来推出了几种 MBL 候选抑制剂,包括处于第三阶段的替尼巴坦和处于第一阶段的 Xeruborbactam。然而,设计出对所有亚类 MBL 都有效的强效抑制剂仍然极具挑战性。本综述不仅总结了β-内酰胺酶的类型和β-内酰胺类抗生素失活的机制,还介绍了针对这些酶的β-内酰胺酶抑制剂的研究成果。这些有关β-内酰胺酶及其抑制剂的详细信息可为新型β-内酰胺酶抑制剂的设计提供宝贵信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Metallo-β-lactamase inhibitors: A continuing challenge for combating antibiotic resistance

β-lactam antibiotics are the most successful and commonly used antibacterial agents, but the emergence of resistance to these drugs has become a global health threat. The expression of β-lactamase enzymes produced by pathogens, which hydrolyze the amide bond of the β-lactam ring, is the major mechanism for bacterial resistance to β-lactams. In particular, among class A, B, C and D β-lactamases, metallo-β-lactamases (MBLs, class B β-lactamases) are considered crucial contributors to resistance in gram-negative bacteria. To combat β-lactamase-mediated resistance, great efforts have been made to develop β-lactamase inhibitors that restore the activity of β-lactams. Some β-lactamase inhibitors, such as diazabicyclooctanes (DBOs) and boronic acid derivatives, have also been approved by the FDA. Inhibitors used in the clinic can inactivate mostly serine-β-lactamases (SBLs, class A, C, and D β-lactamases) but have not been effective against MBLs until now. In order to develop new inhibitors particularly for MBLs, various attempts have been suggested. Based on structural and mechanical studies of MBL enzymes, several MBL inhibitor candidates, including taniborbactam in phase 3 and xeruborbactam in phase 1, have been introduced in recent years. However, designing potent inhibitors that are effective against all subclasses of MBLs is still extremely challenging. This review summarizes not only the types of β-lactamase and mechanisms by which β-lactam antibiotics are inactivated, but also the research finding on β-lactamase inhibitors targeting these enzymes. These detailed information on β-lactamases and their inhibitors could give valuable information for novel β-lactamase inhibitors design.

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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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