Chen Hao, Hu Jie, Chen Peng R, Lan Lefu, Li Zigang, Hicks Leslie M, Dinner Aaron R, He Chuan
Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13586-91. doi: 10.1073/pnas.0803391105. Epub 2008 Aug 29.
MexR is a MarR family protein that negatively regulates multidrug efflux systems in the human pathogen Pseudomonas aeruginosa. The mechanism of MexR-regulated antibiotic resistance has never been elucidated in the past. We present here that two Cys residues in MexR are redox-active. They form intermonomer disulfide bonds in MexR dimer with a redox potential of -155 mV. This MexR oxidation leads to its dissociation from promoter DNA, derepression of the mexAB-oprM drug efflux operon, and increased antibiotic resistance of P. aeruginosa. We show computationally that the formation of disulfide bonds is consistent with a conformation change that prevents the oxidized MexR from binding to DNA. Collectively, the results reveal that MexR is a redox regulator that senses peroxide stress to mediate antibiotic resistance in P. aeruginosa.
MexR是一种MarR家族蛋白，它对人类病原体铜绿假单胞菌中的多药外排系统具有负调控作用。过去从未阐明MexR调节抗生素耐药性的机制。我们在此表明，MexR中的两个半胱氨酸残基具有氧化还原活性。它们在MexR二聚体中形成单体间二硫键，氧化还原电位为-155 mV。这种MexR氧化导致其与启动子DNA解离，解除对mexAB-oprM药物外排操纵子的抑制，并增加铜绿假单胞菌的抗生素耐药性。我们通过计算表明，二硫键的形成与一种构象变化一致，这种构象变化阻止氧化的MexR与DNA结合。总体而言，结果表明MexR是一种氧化还原调节因子，可感知过氧化物应激以介导铜绿假单胞菌中的抗生素耐药性。
