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beta-Lactamases and beta-Lactamase Inhibitors in the 21st Century

机译：21世纪β-内酰胺酶和β-内酰胺酶抑制剂

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The beta-lactams retain a central place in the antibacterial armamentarium. In Gram-negative bacteria, beta-lactamase enzymes that hydrolyze the amide bond of the four-membered beta-lactam ring are the primary resistance mechanism, with multiple enzymes disseminating on mobile genetic elements across opportunistic pathogens such as Enterobacteriaceae (e.g., Escherichia coli) and non-fermenting organisms (e.g., Pseudomonas aeruginosa). beta-Lactamases divide into four classes; the active-site serine beta-lactamases (classes A, C and D) and the zinc-dependent or metallo-beta-lactamases (MBLs; class B). Here we review recent advances in mechanistic understanding of each class, focusing upon how growing numbers of crystal structures, in particular for beta-lactam complexes, and methods such as neutron diffraction and molecular simulations, have improved understanding of the biochemistry of beta-lactam breakdown. A second focus is beta-lactamase interactions with carbapenems, as carbapenem-resistant bacteria are of grave clinical concern and carbapenem-hydrolyzing enzymes such as KPC (class A) NDM (class B) and OXA-48 (class D) are proliferating worldwide. An overview is provided of the changing landscape of beta-lactamase inhibitors, exemplified by the introduction to the clinic of combinations of beta-lactams with diazabicyclooctanone and cyclic boronate serine beta-lactamase inhibitors, and of progress and strategies toward clinically useful MBL inhibitors. Despite the long history of beta-lactamase research, we contend that issues including continuing unresolved questions around mechanism; opportunities afforded by new technologies such as serial femtosecond crystallography; the need for new inhibitors, particularly for MBLs; the likely impact of new beta-lactam:inhibitor combinations and the continuing clinical importance of beta-lactams mean that this remains a rewarding research area. (C) 2019 The Authors. Published by Elsevier Ltd.
机译：β-内酰胺在抗菌铠氨酸中保留了一个中央处理。在革兰氏阴性细菌中，水解四元β-内酰胺环的酰胺键的β-内酰胺酶是初级抗性机制，其中多种酶在机会病原体（例如肠杆菌（例如，大肠杆菌）上的机会病原体上播种和非发酵生物（例如，假单胞菌铜绿假单胞菌）。 β-内酰胺酶分为四个课程;活性位点丝氨酸β-内酰胺（类，C和D）和依赖于锌或金属β-内酰胺酶（MBLS; B类）。在这里，我们审查了对每个类的机械理解的最新进展，重点关注晶体结构的数量，特别是对于β-内酰胺复合物，以及诸如中子衍射和分子模拟的方法，具有改善对β-内酰胺分解的生物化学的理解。第二次重点是与肉豆蔻糖胺酶相互作用与碳癌蛋白酶相互作用，因为鲤鱼抗性细菌是严重的临床关注，碳癌烯 - 水解酶如KPC（A类）NDM（B类）和OXA-48（D类）在全世界繁殖。提供了β-内酰胺酶抑制剂的变化景观的概述，示例是β-内酰胺组合的临床，其中β-内酰胺与二氮杂双环酮和环状硼酸胺丝氨酸β-内酰胺酶抑制剂以及对临床有用的MBL抑制剂的进展和策略。尽管β-内酰胺酶研究历史悠久，但我们争夺了围绕机制持续尚未解决的问题的问题;新技术提供的机会，如串行飞秒晶体学;需要新抑制剂，特别是对于MBLS;新β-内酰胺的可能影响：抑制剂组合和β-内酰胺的持续临床重要性意味着这仍然是一个有益的研究区。 （c）2019年作者。 elsevier有限公司出版

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