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