The oxidative stress regulator, PerR, is required for staphyloferrin B-mediated iron acquisition in Staphylococcus...

Staphylococcus aureus is a globally prevalent gram-positive pathogen that can cause numerous types of infection. Due to host nutritional immunity and iron (Fe) sequestration, S. aureus experiences Fe limitation during infection. To overcome this, S. aureus expresses an arsenal of Fe acquisition systems whose expression is coordinated through the Fe-binding transcriptional regulator, Fur. Here, from a screen to identify S. aureus mutants defective for Fe-restricted growth, we identified several with mutations in perR, encoding a transcriptional regulator involved in resistance to oxidative stress. RNA-seq identified that the most downregulated genes in a perR mutant growing in Fe-restriction are those from the sbn operon that encodes staphyloferrin B biosynthesis. In agreement, perR mutants grew poorly in Fe-deficient media due to deficient staphyloferrin B production. In a subcutaneous model of S. aureus skin infection, S. aureus perR caused significantly smaller lesions, consistent with our finding that this mutant had decreased alpha-hemolysin expression during Fe-restricted growth. These findings are consistent with the hypothesis that PerR acts to fine-tune access to Fe ostensibly to avoid Fe-dependent toxicity. The importance of the PerR function to S. aureus was further highlighted by examination of over 8,000 human bloodstream isolates of S. aureus, showing that the PerR sequence was highly conserved. Together, these findings demonstrate the importance of PerR to S. aureus in providing an additional level of regulation of Fe homeostasis beyond Fur-dependent Fe sensing.IMPORTANCEStaphylococcus aureus is a notoriously antibiotic-resistant human pathogen and has the potential to cause a myriad of potentially life-threatening infections. Understanding the intricacies of S. aureus pathogenesis in the host will underpin the development of novel therapeutic approaches that target bacterial virulence mechanisms rather than essential cellular processes. The significance of our research lies in identifying how S. aureus regulates Fe acquisition in response to environmental signals, providing further insight into nutrient sensing and acquisition at the host-pathogen interface to facilitate the development of therapeutics that may target this process.