Roles of Salmonella multidrug efflux pumps in tigecycline resistance
Roles of Salmonella multidrug efflux pumps in tigecycline resistance
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DOI：
10.1093/jac/dkq421
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发表时间：
2011-01-01
影响因子：
5.2
通讯作者：
Nishino, Kunihiko
中科院分区：
文献类型：
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作者：
Horiyama, Tsukasa;Nikaido, Eiji;Nishino, Kunihiko
肠炎沙门氏菌对替吉环素敏感性降低的报道已有报道。在本研究中，我们试图阐明沙门氏菌多药外排泵和AcrAB调节剂在替格环素耐药中的作用。我们通过测定沙门氏菌多药外排泵和AcrAB调节剂过度产生或缺失菌株的MIC来研究多药外排泵和AcrAB调节剂在替环素和其他甘环素类药物耐药中的作用。从野生型菌株ATCC14028S中分离到的鼠伤寒沙门氏菌对9-(N，N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline)米诺环素、多西环素和四环素产生抗性，但不影响替格环素的抗性。AcrAB缺失导致菌株对替吉环素和其他甘环素类药物的敏感性显著增加。携带acrAB或acrEF基因的质粒恢复了acrAB缺失突变体对所有测试化合物的敏感性增加。缺失acrAB的正调控因子RAMA，略微增加了对替格环素的易感性。RAMA的过度表达和RAMA抑制物ramR的缺失导致对所有受试化合物的敏感性降低。在AcrB缺失的背景下没有观察到这种受raM A或ramR调控的表型。AcrAB和AcrEF使沙门氏菌对替环素和四环素衍生物产生耐药性。RAMA和RamR也以AcrAB依赖的方式参与对替格环素的耐药性。
Salmonella enterica strains exhibiting decreased susceptibility to tigecycline have been reported. In this study, we sought to elucidate the roles of Salmonella multidrug efflux pumps and AcrAB regulators in tigecycline resistance.We examined the involvement of multidrug efflux pumps and AcrAB regulators in resistance to tigecycline and other glycylcyclines by determining the MICs of the drugs for Salmonella multidrug efflux pump and AcrAB regulator-overproducing or -deleted strains. Strains of S. enterica serovar Typhimurium derived from the wild-type strain ATCC 14028s were used in this study.A plasmid carrying the tet gene conferred resistance to 9-(N,N-dimethylglycylamido)-6-demethyl-6-deoxytetracycline ('DMG-DMDOT') minocycline, doxycycline and tetracycline, but does not affect tigecycline resistance. Deletion of acrAB resulted in strains with significantly increased susceptibility to tigecycline and other glycylcyclines. Plasmids carrying the acrAB or acrEF gene restored increased susceptibility of the acrAB-deleted mutant to all tested compounds. Deletion of ramA, a positive regulator of acrAB, slightly increased susceptibility to tigecycline. Overexpression of ramA and deletion of ramR, a repressor of ramA, resulted in decreased susceptibility to all tested compounds. This phenotype, modulated by ramA or ramR, was not observed in the acrB-deleted background.AcrAB and AcrEF confer resistance to tigecycline and tetracycline derivatives in Salmonella. RamA and RamR are also involved in resistance to tigecycline in an AcrAB-dependent manner.