Involvement of reductases I ru O and N tr A in iron acquisition by S taphylococcus aureus

Summary To obtain host iron, S taphylococcus aureus secretes siderophores staphyloferrin A ( SA ) or staphyloferrin B ( SB ), and accesses heme iron through use of iron‐regulated surface determinant proteins. While iron transport in S . aureus is well documented, there is scant information about proteins required to access iron from complexes in the cytoplasm. In vitro studies identified a pyridine nucleotide‐disulfide oxidoreductase, named I ru O , as an electron donor for the heme monooxygenases I sd G and IsdI, promoting heme degradation. Here, we show that an iru O mutant was not debilitated for growth on heme, suggesting involvement of another reductase. N tr A is an iron‐regulated nitroreductase and, as with the iru O mutant, a ntr A mutant grew on heme comparable with wild type ( WT ). In contrast, a iru O   ntr A double mutant was severely debilitated for growth on heme, a phenotype that was complemented by expression of either iru O or ntr A   in trans , demonstrating their overlapping role in heme‐iron utilization. Contrasting the involvement of multiple reductases for heme iron utilization, ntrA was shown essential for iron utilization using SA, although not SB or other siderophores tested, and an iruO mutant was incapable of deferoxamine‐mediated growth. Accordingly, virulence of WT S . aureus , but not an iru O mutant, was enhanced in mice receiving deferoxamine.