Thai Van C, Stubbs Keith A, Sarkar-Tyson Mitali, Kahler Charlene M
The Marshall Center for Infectious Diseases Research and Training, School of Biomedical Sciences, University of Western Australia, Crawley, WA 6009, Australia.
School of Molecular Sciences, University of Western Australia, Crawley, WA 6009, Australia.
Antibiotics (Basel). 2023 Aug 29;12(9):1382. doi: 10.3390/antibiotics12091382.
Antibiotic resistance caused by multidrug-resistant (MDR) bacteria is a major challenge to global public health. Polymyxins are increasingly being used as last-in-line antibiotics to treat MDR Gram-negative bacterial infections, but resistance development renders them ineffective for empirical therapy. The main mechanism that bacteria use to defend against polymyxins is to modify the lipid A headgroups of the outer membrane by adding phosphoethanolamine (PEA) moieties. In addition to lipid A modifying PEA transferases, Gram-negative bacteria possess PEA transferases that decorate proteins and glycans. This review provides a comprehensive overview of the function, structure, and mechanism of action of PEA transferases identified in pathogenic Gram-negative bacteria. It also summarizes the current drug development progress targeting this enzyme family, which could reverse antibiotic resistance to polymyxins to restore their utility in empiric therapy.
多重耐药（MDR）细菌引起的抗生素耐药性是全球公共卫生面临的一项重大挑战。多粘菌素越来越多地被用作治疗多重耐药革兰氏阴性菌感染的最后一线抗生素，但耐药性的产生使其在经验性治疗中失效。细菌抵御多粘菌素的主要机制是通过添加磷酸乙醇胺（PEA）部分来修饰外膜的脂质A头部基团。除了修饰脂质A的PEA转移酶外，革兰氏阴性菌还拥有修饰蛋白质和聚糖的PEA转移酶。本综述全面概述了在致病性革兰氏阴性菌中鉴定出的PEA转移酶的功能、结构和作用机制。它还总结了目前针对该酶家族的药物开发进展，这可能逆转对多粘菌素的抗生素耐药性，以恢复其在经验性治疗中的效用。
