Enzyme targets for drug design of new anti-virulence therapeutics
Enzyme targets for drug design of new anti-virulence therapeutics
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DOI：
10.1016/j.sbi.2018.08.010
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发表时间：
2018-12-01
影响因子：
6.8
通讯作者：
Vrielink, Alice
中科院分区：
文献类型：
--
作者：
Kahler, Charlene M.;Sarkar-Tyson, Mitali;Vrielink, Alice
社会因抗生素的使用而受益匪浅。不幸的是，这些有价值的分子的滥用导致了抗生素耐药性的增加，这是一个重大的全球和公共卫生问题。这种耐药性以及抗生素开发对少数生物靶点的依赖强调了对新靶点的需求。通过合理的结构引导方法指导新型抗菌药物开发的一个关键方面是了解特定目标生物靶标的分子结构。在这里，我们概述了参与蛋白质折叠、肽聚糖生物合成和细胞壁修饰的细菌毒力酶靶标的结构。这些包括硫醇二硫化物氧化还原酶途径的酶（DSB 酶）、肽基脯氨酸顺/反式异构酶（Mips）、Mur 途径的酶以及参与脂多糖修饰的酶（EptA 和 ArnT）。我们还介绍了这些靶点的抑制剂设计用于开发新型抗毒力治疗剂的进展。
Society has benefitted greatly from the use of antibiotics. Unfortunately, the misuse of these valuable molecules has resulted in increased levels of antibiotic resistance, a major global and public health issue. This resistance and the reliance on a small number of biological targets for the development of antibiotics emphasizes the need for new targets. A critical aspect guiding the development of new antimicrobials through a rational structure-guided approach is to understand the molecular structures of specific biological targets of interest. Here we give an overview of the structures of bacterial virulence enzyme targets involved in protein folding, peptidoglycan biosynthesis and cell wall modification. These include enzymes of the thiol-disulphide oxidoreductase pathway (DSB enzymes), peptidyl-proly cis/trans isomerases (Mips), enzymes from the Mur pathway and enzymes involved in lipopolysaccharide modification (EptA and ArnT). We also present progress towards inhibitor design of these targets for the development of novel anti-virulence therapeutic agents.