分子模拟在多黏菌素药理机制研究中的应用  

Applications of Molecular Dynamics Simulations in The Research of Polymyxin Pharmacology

作　　者：蒋绪恺 肖敏[1] 王禄山[2] JIANG Xu-Kai;XIAO Min;WANG Lu-Shan(National Glycoengineering Research Center,Shandong University,Qingdao 266237,China;State Key Laboratory of Microbial Technology,Shandong University,Qingdao 266237,China)

机构地区：[1]山东大学国家糖工程技术研究中心,青岛266237 [2]山东大学微生物技术国家重点实验室,青岛266237

出　　处：《生物化学与生物物理进展》2023年第5期919-925,共7页Progress In Biochemistry and Biophysics

基　　金：国家重点研发计划(2018YFA0902000,2021YFC2103100);国家自然科学基金(32100022);山东省自然科学基金(ZR2022QC014)资助项目。

摘　　要：多黏菌素是一种膜靶向的脂肽类抗生素,是临床上治疗革兰氏阴性多重耐药菌感染的最后一道防线。通过与脂多糖相互作用,多黏菌素破坏细菌外膜结构并导致细菌死亡。然而,受限于生物化学和结构生物学手段对细胞膜-药物相互作用的表征能力,目前对多黏菌素药理机制的认识还不充分,从而限制了新一代多黏菌素药物的设计和开发。为此,本文总结了近年来利用分子动力学方法对细胞膜系统与多黏菌素相互作用的研究进展,为深入理解多黏菌素药理机制与细胞膜系统的内在联系,加快新型抗生素药物研发提供新思路。As a kind of membrane-active lipopeptide antibiotics,polymyxins are the last-line therapy against multidrug-resistant Gram-negative pathogens.Through interacting with the lipopolysaccharide molecules,polymyxins disorganize the structure of bacterial outer membrane,and finally lead to the cell death.Nevertheless,the precise mechanisms of polymyxin pharmacology remain largely unknown,which is mainly due to the limited ability of current biochemical and structural approaches to characterize the interaction between cell membranes and drugs.This in turn significantly hinders the design and development of new-generation polymyxins.In recent years,molecular dynamics simulations have been successfully applied in the field of polymyxin pharmacology.In particular,a series of simulation models,including bacterial membranes-polymyxins,and human cell membranepolymyxins,has been developed and tested.Previous studies have shown that polymyxin adopted a unique folded conformation in bacterial outer membrane,which played a key role in the antimicrobial activity of polymyxins.Further,various lipopolysaccharide modifications could change the structural and physical properties of bacterial outer membrane and thereby confer polymyxin resistance to bacteria.Moreover,recent studies revealed that polymyxins may disrupt the membrane of renal tubular cells,and also attenuate the function of different ion channels,which provide a clue to understand the detailed mechanism of polymyxin-induced nephrotoxicity.In this review,we summarized the applications of molecular dynamics simulations in the interaction of polymyxins with different biological membranes,with the aim to refresh our understanding of the link between polymyxin pharmacology and cell membranes and to provide mechanistic guides for the future design of novel antimicrobial drugs.

关 键 词：细菌耐药 细胞膜 多黏菌素 分子动力学模拟 抗生素设计 

分 类 号：Q61[生物学—生物物理学] R96[医药卫生—药理学]