革兰氏阴性菌多药外排泵MacAB-TolC的功能与结构

Function and Structure of the Multidrug Efflux Pump MacAB-TolC from Gram-negative Bacteria

病原菌日益增长的多药耐药性已成为人类健康和生命的主要威胁之一。多药外排泵介导的药物主动外排是细菌产生耐药性的主要原因之一,给感染性疾病的防治带来了极大挑战。深入研究多药外排泵,了解其作用机制,揭示药物结合位点,可以为临床抗感染治疗提供新思路。在革兰氏阴性菌中,一些多药外排泵形成跨越细菌胞外被膜的三联复合物。MacAB-TolC是普遍存在于革兰氏阴性菌中的ABC家族三联外排泵,在近些年逐渐被关注。本文综述了关于MacAB-TolC外排泵的功能与结构研究以及相应抑制剂研发方面的进展。MacAB-TolC外排泵的底物种类多样,包含抗生素、毒力因子以及代谢产物。本文据此将MacAB-TolC外排泵的功能归纳为3类:耐药功能、病理功能和生理功能,并对相应功能分别进行了阐述。在结构研究方面,本文总结了MacAB-TolC外排泵单个组分的晶体结构和组装完全的MacAB-TolC三联外排泵的冷冻电镜单颗粒结构,并对结构数据所揭示的MacAB-TolC外排泵发挥功能的机制进行了论述。最后,本文介绍了MacAB-TolC外排泵抑制剂的最新研究进展,指出解析MacAB-TolC的原位结构,以及MacB结合底物/抑制剂的晶体结构是未来的研究方向,可为外排泵抑制剂的设计和研发提供准确的靶点。

The emerging multidrug resistance in pathogenic bacteria has become one of the major threats to human health and life.Drug efflux mediated actively by the multidrug efflux pump is one of the main reasons for bacteria resistance,which brings great challenges to the prevention and treatment of infectious diseases.Therefore research of the multidrug efflux pumps and understanding their functional mechanisms as well as drug binding sites could provide new insights into the clinical anti-infection treatments.In Gram-negative bacteria,some multidrug efflux pumps form tripartite assemblies that span the cell envelope.MacAB-TolC,a tripartite efflux pump of the ABC(ATP-binding cassette)family,is commonly found in the Gram-negative bacteria and has caught more and more attention in recent years.This paper reviews the advances in the function and structure of the MacAB-TolC efflux pump and the development of corresponding inhibitors.The MacAB-TolC efflux pump has a variety of substrates,including antibiotics,virulence factors and metabolites.Based on this,this paper will elucidate the function of the MacABTolC efflux pump on drug resistance,pathology,and physiology.In terms of structural study,this paper summarizes the crystal structures of the single component of MacAB-TolC as well as the cryo-EM single particle structure of the fully assembled tripartite efflux pump MacAB-TolC,and discusses the function mechanism of MacAB-TolC efflux pump revealed by the structural data.Finally,we introduce the latest research progress of MacAB-TolC efflux inhibitors and point out that the determination of the in situ structure of MacAB-TolC and the crystal structures of MacB bound with substrate/inhibitor is the future research direction,which can provide accurate targets for the design and development of efflux pump inhibitors.