title: The Pseudomonas aeruginosa multidrug efflux regulator MexR uses an oxidation-sensing mechanism.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Peng R
authors.initials: PR
authors.lastname: Chen
authors.forename: Lefu
authors.initials: L
authors.lastname: Lan
authors.forename: Zigang
authors.initials: Z
authors.lastname: Li
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Hicks
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.forename: Chuan
authors.initials: C
authors.lastname: He