School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia.
School of Molecular Sciences, University of Western Australia, 35 Stirling Highway, Perth, WA 6009, Australia.
J Mol Biol. 2020 Aug 21;432(18):5184-5196. doi: 10.1016/j.jmb.2020.04.022. Epub 2020 Apr 27.
A wide variety of antibiotics are targeted to the bacterial membrane due to its unique arrangement and composition relative to the host mammalian membranes. By modification of their membranes, some gram-negative pathogens resist the action of antibiotics. Lipid A phosphoethanolamine transferase (EptA) is an intramembrane enzyme that modifies the lipid A portion of lipopolysaccharide/lipooligosaccharide by the addition of phosphoethanolamine. This modification reduces the overall net-negative charge of the outer membrane of some gram-negative bacteria, conferring resistance to polymyxin. This resistance mechanism has resulted in a global public health issue due to the increased use of polymyxin as last-resort antibiotic treatments against multi-drug-resistant pathogens. Studies show that, without EptA, pathogenic bacteria become more sensitive to polymyxin and to clearance by the host immune system, suggesting the importance of this target enzyme for the development of novel therapeutic agents. In this review, EptA will be discussed comprehensively. Specifically, this review will cover the regulation of eptA expression by the two component systems PmrA/PmrB and PhoP/PhoQ, the site of modification on lipid A, the structure and catalytic mechanism of EptA in comparison to MCR-1 and Escherichia coli alkaline phosphatase, and the host immune system's response to lipid A modification by EptA. The overarching aim of this review is to provide a comprehensive overview of polymyxin resistance mediated by EptA.
由于细菌膜的独特排列和组成与宿主哺乳动物膜不同，因此有各种各样的抗生素针对细菌膜。通过改变它们的膜，一些革兰氏阴性病原体对抗生素的作用产生了抗性。脂质 A 磷酸乙醇胺转移酶（EptA）是一种内膜酶，通过添加磷酸乙醇胺来修饰脂多糖/脂寡糖的脂质 A 部分。这种修饰降低了某些革兰氏阴性细菌外膜的总净负电荷，从而赋予了对多粘菌素的抗性。由于多粘菌素作为治疗多药耐药病原体的最后手段抗生素的使用增加，这种耐药机制导致了一个全球性的公共卫生问题。研究表明，如果没有 EptA，致病性细菌对多粘菌素和宿主免疫系统的清除作用变得更加敏感，这表明该靶酶对于开发新型治疗剂的重要性。在这篇综述中，将全面讨论 EptA。具体来说，本综述将涵盖两个二元系统 PmrA/PmrB 和 PhoP/PhoQ 对 eptA 表达的调节、脂质 A 上的修饰位点、EptA 与 MCR-1 和大肠杆菌碱性磷酸酶的结构和催化机制，以及宿主免疫系统对 EptA 修饰脂质 A 的反应。本综述的总体目标是提供 EptA 介导的多粘菌素耐药的全面概述。
