多重耐药沙门氏菌AcrB突变对AcrAB-TolC外排泵转运功能的影响

Infections caused by superbugs resistant to multiple drugs lead to global panic. At the moment, development of multi-drug resistance reversal agents is hot spot of present research. AcrAB-TolC efflux system, which can expel a wide range of structurally diverse antibiotics out of the cell, is the main mechanism of multi-drug resistance in gram negative bacteria. AcrAB-TolC pump is a tripartite system, constituted of an inner membrane transporter AcrB, outer membrane protein TolC, and a periplasmic adaptor protein AcrA. The overexpression of this system can confer multiple resistant to antibiotics. The transporter AcrB captures and transfers drug molecules from the periplasm, showing an extremely wide substrate specificity. Mutations within AcrB residues will change the pumping activity of AcrAB-TolC. In this study, we will focus on the mutations presented in AcrB of multi-drug resistant Salmonella from clinic settings, exploring the following scientific issues: to explore the effect of AcrB mutants on the efflux activity of AcrAB-TolC via analysis the protein structure alterations of AcrB mutant, investigation the way of drug binding and transferring within AcrB mutant. This study provide theoretical foundation for design multi-drug resistant reversal agents , which would be novel strategies for treatment of infections causing by multi-drug resistance Salmonella.

耐抗生素"超级细菌"（即多重耐药菌）引起的感染已引起全球恐慌。寻找多药耐药逆转剂而重新再利用现有耐受抗生素成为研究新热点。AcrAB-TolC外排系统能将许多不同结构的抗生素从细菌细胞内排出，是引起革兰氏阴性菌多重耐药的主要机制。AcrAB-TolC中，内膜组分AcrB与膜融合蛋白AcrA和外膜蛋白TolC形成一个跨越内膜和外膜的三组分系统。AcrB蛋白含有药物结合和转运区域，其氨基酸残基发生突变，将影响AcrAB-TolC外排功能。本课题以多重耐药沙门氏菌突变的AcrB为靶点，通过解析AcrB突变对药物结合、转运的影响，阐明突变对AcrAB-TolC外排功能的影响。研究结果将为寻找和设计新型多药耐药逆转剂提供作用靶点，为治疗多重耐药菌感染提供新策略。