Variable staphyloxanthin production by Staphylococcus aureus drives strain-dependent effects on diabetic wound-healing outcomes

Strain-level variation in Staphylococcus aureus is a factor that contributes to disease burden and clinical out-comes in skin disorders and chronic wounds. However, the microbial mechanisms that drive these variable host responses are poorly understood. To identify mechanisms underlying strain-specific outcomes, we perform high-throughput phenotyping screens on S. aureus isolates cultured from diabetic foot ulcers. Iso-lates from non-healing wounds produce more staphyloxanthin, a cell membrane pigment. In murine diabetic wounds, staphyloxanthin-producing isolates delay wound closure significantly compared with staphyloxan-thin-deficient isolates. Staphyloxanthin promotes resistance to oxidative stress and enhances bacterial sur-vival in neutrophils. Comparative genomic and transcriptomic analysis of genetically similar clinical isolates with disparate staphyloxanthin phenotypes reveals a mutation in the sigma B operon, resulting in marked dif-ferences in stress response gene expression. Our work illustrates a framework to identify traits that underlie strain-level variation in disease burden and suggests more precise targets for therapeutic intervention in S. aureus-positive wounds.