The multiple antibiotic resistance regulator MarR is a copper sensor in Escherichia coli

Drugs and antibiotics induce oxidation and mobilization of membrane-bound copper( I ) ions to copper( II ) species within the E. coli cytosol, causing oxidation of a single cysteine residue of the multiple antibiotic-resistance regulator MarR, that leads to formation of disulfide-bonded MarR tetramers and release of dimers from sites of transcriptional activity. 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.