Cysteine biosynthesis, oxidative stress and antibiotic resistance in Salmonella typhimurium

The efficacy of antibiotics varies under different growth conditions due to the induction of specific or more general defense pathways, but the mechanisms are not completely understood. Actively swarming Salmonella show elevated resistance to many types of antibiotics. Previously, we had shown that cysteine biosynthesis was important for the induced antibiotic resistance phenotype of swarm cells. Here we examine the connection of cysteine to oxidative stress and demonstrate that the antioxidant properties of cysteine or cysteine-derived metabolites contribute to the antibiotic resistance in both vegetative and swarm cell populations. We observed that cys auxotrophs were oxidatively stressed, and in wild-type cells expression of the cys regulon was induced during periods of oxidative stress. In swarm cells, we found a 6-fold increase in reduced glutathione compared to swim cells and a corresponding increased resistance to oxidants. Wild-type and cys auxotrophs exhibited the same sensitivities to gentamicin, polymyxin and ciprofloxacin when grown anaerobically, suggesting that induced oxidative stress defense was contributing to elevated antibiotic resistance in swarm cells aerobically. Induction of the CysB regulon by addition of exogenous inducer resulted in elevated antibiotic resistance independently of swarming.