Biotin sulfoxide reductase contributes to oxidative stress tolerance and virulence in Salmonella enterica serovar Typhimurium

Oxidative stress converts sulfur residues of molecules like biotin and methionine into their oxidized forms. Here we show that the biotin sulfoxide reductase BisC of Salmonella enterica serovar Typhimurium (S. Typhimurium) repairs both oxidized biotin and oxidized methionine. Exposure to H2O2 in vitro reduced survival of a S. Typhimurium Delta bisC mutant. Furthermore, replication of the Delta bisC mutant inside IFN-gamma activated macrophages was reduced. In vitro tolerance of the mutant to H2O2 was restored by plasmids carrying either bisC or msrA; the latter encodes a methioinine sulfoxide reductase. In contrast, the proliferation defect inside IFN-gamma activated macrophages was rescued by bisC but not by msrA. Thus growth of the Delta bisC mutant in IFN-gamma activated macrophages required repair of oxidized biotin. Both the Delta bisC and a biotin auxotrophic (Delta bioB) mutant were attenuated in mice, suggesting that besides biotin biosynthesis, biotin repair was essential for virulence of S. Typhimurium in vivo. Attenuation of the Delta bisC mutant was more pronounced in 129 mice that produce a stronger oxidative response. These results show that BisC is essential for full virulence of Salmonella by contributing to the defence of S. Typhimurium against host-derived stress, and provides an attractive drug target since it is not present in mammals.