Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium
Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium
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DOI：
10.1111/j.1365-2958.2005.04940.x
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Groisman, EA
中科院分区：
文献类型：
--
作者：
Nishino, K;Latifi, T;Groisman, EA
药物外排系统在几种革兰氏阴性物种对多种有害化合物的抗性中起主要作用。在这里，我们报告了沙门氏菌突变体的耐药性和毒力表型，这些突变体在耐药-结节分裂（RND）型系统和/或在属于主要促进剂（MFS）、多药和有毒化合物挤出（MATE）和atp结合盒（ABC）超家族的药物外排系统中存在缺陷。我们确定了9种潜在的药物转运体有助于沙门氏菌的耐药性，并发现沙门氏菌特异性MdsABC系统赋予了对多种有毒化合物的抗性。rnd型MdsAB系统既可以与编码在同一操纵子中的MdsC一起工作，也可以与作为外膜成分的TolC一起工作。虽然沙门氏菌EmrAB、MdfA和MdtK的氨基酸序列与大肠杆菌同源物90%相同，但沙门氏菌转运体的药物特异性与报道的等效大肠杆菌转运体不同。当小鼠通过口服途径接种沙门氏菌时，缺失macAB基因可减弱沙门氏菌的毒力，并且缺乏所有药物外排系统的菌株是无毒的。macb药物外排系统基因的启动子区域含有一个反应调节因子PhoP的结合位点，其功能是抑制macb的转录。PhoP/PhoQ双组分系统是沙门氏菌毒力的主要调节因子，这强调了药物外排系统与毒力之间的联系。
Drug efflux systems play a major role in resistance to a wide range of noxious compounds in several Gram negative species. Here, we report the drug resistance and virulence phenotypes of Salmonella mutants defective in either resistance-nodulation-division (RND)-type systems and/or in drug efflux systems belonging to the major facilitator (MFS), multidrug and toxic compound extrusion (MATE), and ATP-binding cassette (ABC) superfamilies. We determined that nine potential drug transporters contribute to drug resistance of Salmonella and found that the Salmonella-specific MdsABC system conferred resistance to a variety of toxic compounds. The RND-type MdsAB system could function with either MdsC, which is encoded in the same operon, or TolC as the outer membrane component. Although the Salmonella EmrAB, MdfA and MdtK are 90% identical in their amino acid sequences to their Escherichia coli homologues, the drug specificity of Salmonella transporters was different from that reported for equivalent E. coli transporters. Deletion of the macAB genes attenuated Salmonella virulence and a strain lacking all drug efflux systems was avirulent when mice were inoculated by the oral route. The promoter region of the macAB drug efflux system genes harbours a binding site for the response regulator PhoP, which functions to repress macAB transcription. The PhoP/PhoQ two-component system is a major regulator of Salmonella virulence, which underscores the connection between drug efflux systems and virulence.