Salmonella uses sulfate reductases with unique catalytic activity to promote gut colonization in mice

Abstract

Non-typhoidal Salmonella use molybdenum cofactor-containing MopB- or DMSO reductase-family members to respire chemically diverse substrates, including formate, nitrate and methionine sulfoxide, during infection. The DmsABC enzymatic complex encodes one such DMSO reductase to promote oxidative stress resistance. The Salmonella genome encodes several gene paralogues but their role in virulence is unclear. Here we characterize three Salmonella MopB-family extracytoplasmic sulfate reductases, which we call Xsr1A, Xsr2A and Xsr3A. Infection experiments in mice and macrophages show that these sulfate reductases support Salmonella growth and virulence in the gut and during systemic infection, countering the oxidative effects of host respiratory burst activity. Further experiments show that they are molybdenum cofactor-independent enzymes, and instead depend on the nearby redox-active [4Fe–4S] prosthetic group for catalytic activity. Orthologues of these sulfate reductases were found across distant evolutionary branches, suggesting that [4Fe–4S]-dependent catalysis may occur across the ubiquitous MopB superfamily. Our findings offer insights into the modular evolution of redox centres in the widespread MopB superfamily. Extracytoplasmic MopB-family sulfate reductases using Fe–S clusters instead of molybdenum as a cofactor enable sulfate assimilation in Salmonella to support gut colonization and virulence, and help to counter host-imposed oxidative stress.