title: The multiple antibiotic resistance regulator MarR is a copper sensor in Escherichia coli.
abstract: 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.
authors.affiliation: 1] Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2].
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Hao
authors.affiliation: 1] Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] [3].
authors.forename: Hubing
authors.initials: H
authors.lastname: Lou
authors.affiliation: Peking-Tsinghua Center for Life Sciences, Beijing, China.
authors.forename: Rongfeng
authors.initials: R
authors.lastname: Zhu
authors.affiliation: College of Biological Sciences, China Agricultural University, Beijing, China.
authors.forename: Jiuhe
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Dianmu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 1] Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Boxuan Simen
authors.initials: BS
authors.lastname: Zhao
authors.affiliation: International Curriculum Center, High School affiliated to Renmin University, Beijing, China.
authors.forename: Shizhe
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of California-Berkeley, Berkeley, California, USA.
authors.forename: Jefferson
authors.initials: J
authors.lastname: Chan
authors.affiliation: 1] Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, Illinois, USA. [3] Shanghai Universities E-Institute for Chemical Biology, Shanghai, China.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: 1] Synthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China. [2] Peking-Tsinghua Center for Life Sciences, Beijing, China. [3] Shanghai Universities E-Institute for Chemical Biology, Shanghai, China.
authors.forename: Peng R
authors.initials: PR
authors.lastname: Chen
mesh_terms: D003300:Copper / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism*; D008958:Models, Molecular; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D029968:Escherichia coli Proteins; C080004:MarR protein, E coli; D012097:Repressor Proteins; D003300:Copper