Sulfane Sulfur Is An Intrinsic Signal Activating Mexr-Regulated Antibiotic Resistance Inpseudomonas Aeruginosa

Pseudomonas aeruginosaPAO1, an opportunistic human pathogen, deploys several strategies to resist antibiotics. It uses multidrug efflux pumps, including the MexAB-OprM pump, for antibiotic resistance, and it also produces hydrogen sulfide (H2S) that provides some defense against antibiotics. MexR functions as a transcriptional repressor of themexAB-oprMoperon. MexR responds to oxidative stresses caused by antibiotic exposure, and it also displays a growth phase-dependent derepression of themexAB-oprMoperon. However, the intrinsic inducer has not been identified. Here, we report thatP. aeruginosaPAO1 produced sulfane sulfur, including glutathione persulfide and inorganic polysulfide, produced from either H2S oxidation or from L-cysteine metabolism. Sulfane sulfur directly reacted with MexR, forming di- and trisulfide cross-links between two Cys residues, to derepress themexAB-oprMoperon. Levels of cellular sulfane sulfur andmexAB-oprMexpression varied during growth, and both reached the maximum during the stationary phase of growth. Thus, self-produced H2S and sulfane sulfur may facilitate antibiotic resistance via inducing the expression of antibiotic resistance genes.