TY - JOUR
T1 - The multiple antibiotic resistance regulator MarR is a copper sensor in Escherichia coli
AU - Hao, Ziyang
AU - Lou, Hubing
AU - Zhu, Rongfeng
AU - Zhu, Jiuhe
AU - Zhang, Dianmu
AU - Zhao, Boxuan Simen
AU - Zeng, Shizhe
AU - Chen, Xing
AU - Chan, Jefferson
AU - He, Chuan
AU - Chen, Peng R.
N1 - Funding Information:
We thank J. Rosner (National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health) for providing the strains of M2073 (WT E. coli) and M2076 (marRAB mutant strains) bearing the marR::lacZ reporter, J.J. Collins (Department of Biomedical Engineering, Boston University) for providing the pL(lexO)-GFP reporter, C.J. Chang (College of Chemistry, University of California–Berkeley) for providing the Cu(I)-specific fluorescent probe CS-1 and S.F. Reichard for editing. The E. coli WT (K12) strain (BW25113) and all of the single-gene deletion mutants were obtained from the National BioResource Project (National Institute of Genetics, Japan). We also thank the staff members of the Shanghai Synchrotron Radiation Facility and the Beijing Synchrotron Radiation Facility. This work was supported by research grants from the National Basic Research Foundation of China (2010CB912302 and 2012CB917301 to P.R.C.; 2011CB809103 to C.H.), the National Natural Science Foundation of China (21225206, 91013005 and 21001010 to P.R.C.), the US National Science Foundation (CHE-1213598 to C.H.) and the E-Institutes of Shanghai Municipal Education Commission (project number E09013 to C.H. and P.R.C.).
PY - 2014/1
Y1 - 2014/1
N2 - The widely conserved multiple antibiotic resistance regulator (MarR) family of transcription factors modulates bacterial detoxification in response to diverse antibiotics, toxic chemicals or both. The natural inducer for Escherichia coli MarR, the prototypical transcription repressor within this family, remains unknown. Here we show that copper signaling potentiates MarR derepression in E. coli. Copper(II) oxidizes a cysteine residue (Cys80) on MarR to generate disulfide bonds between two MarR dimers, thereby inducing tetramer formation and the dissociation of MarR from its cognate promoter DNA. We further discovered that salicylate, a putative MarR inducer, and the clinically important bactericidal antibiotics norfloxacin and ampicillin all stimulate intracellular copper elevation, most likely through oxidative impairment of copper-dependent envelope proteins, including NADH dehydrogenase-2. This membrane-associated copper oxidation and liberation process derepresses MarR, causing increased bacterial antibiotic resistance. Our study reveals that this bacterial transcription regulator senses copper(II) as a natural signal to cope with stress caused by antibiotics or the environment.
AB - The widely conserved multiple antibiotic resistance regulator (MarR) family of transcription factors modulates bacterial detoxification in response to diverse antibiotics, toxic chemicals or both. The natural inducer for Escherichia coli MarR, the prototypical transcription repressor within this family, remains unknown. Here we show that copper signaling potentiates MarR derepression in E. coli. Copper(II) oxidizes a cysteine residue (Cys80) on MarR to generate disulfide bonds between two MarR dimers, thereby inducing tetramer formation and the dissociation of MarR from its cognate promoter DNA. We further discovered that salicylate, a putative MarR inducer, and the clinically important bactericidal antibiotics norfloxacin and ampicillin all stimulate intracellular copper elevation, most likely through oxidative impairment of copper-dependent envelope proteins, including NADH dehydrogenase-2. This membrane-associated copper oxidation and liberation process derepresses MarR, causing increased bacterial antibiotic resistance. Our study reveals that this bacterial transcription regulator senses copper(II) as a natural signal to cope with stress caused by antibiotics or the environment.
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U2 - 10.1038/nchembio.1380
DO - 10.1038/nchembio.1380
M3 - Article
C2 - 24185215
AN - SCOPUS:84891013485
SN - 1552-4450
VL - 10
SP - 21
EP - 28
JO - Nature chemical biology
JF - Nature chemical biology
IS - 1
ER -