In Staphylococcus aureus, Fur is an interactive regulator with PerR, contributes to virulence, and is necessary for oxidative stress resistance through positive regulation of catalase and iron homeostasis

The Staphylococcus aureus genome encodes three ferric uptake repressor (Fur ) homologues: Fur, PerR, and Zur. To determine the exact role of Fur in S. aureus, we inactivated the fur gene by allelic replacement using a tetracyc line resistance cassette, creating strain MJH010 (fur) The mutant had a gro wth defect in rich medium, and this defect was exacerbated in metal-deplete d CL medium, This growth defect was partially suppressed by manganous ion, a metal ion with known antioxidant properties. This suggests that the fur m utation leads to an oxidative stress condition, Indeed, MJH010 (fur) has re duced levels of catalase activity resulting from decreased katA transcripti on. Using a katA-lacZ fusion we have determined that Fur functions, either directly or indirectly, as an iron-dependent positive regulator of katA exp ression, Transcription of katA is coregulated by Fur and PerR, since in MJH 010 (fur) transcription was still repressed by manganese while transcriptio n in MJH201 (fur perR) was unresponsive to the presence of iron or manganes e, Siderophore biosynthesis was repressed by iron in 8325-4 (wild-type) but in MJH010 (fur) was constitutive. A number of putative Fur-regulated genes were identified in the incomplete genome databases using known S. aureus F ur box sequences. Of those tested, the sstABCD and sirABC operons and the f huD2 and orf4 genes were found to have Fur-regulated expression, MJH010 (fu r) was attenuated (P < 0.04) in a murine skin abscess model of infection, a s was double-mutant MJH201 (fur perR) (P < 0.03), This demonstrates the imp ortance in vivo of iron homeostasis and oxidative stress resistance regulat ion in S. aureus.