Differential Pathogenic and Commensal Response of Staphylococcus aureus and Staphylococcus epidermidis Towards Chemical Signals of Human Skin

ABSTRACT Pathogenic Staphylococcus aureus and commensal Staphylococcus epidermidis encounter acidic pH and C16 fatty acids on human skin, but S. aureu s uniquely has a complete fad pathway for metabolism of saturated C16:0 palmitic acid. We now report on significant differences in their response to C16 fatty acids during growth at pH 5.5. Unsaturated palmitoleic acid C16:1 was more toxic to S. aureus , but toxicity was mitigated by saturated C16:0. Consistent with a functional fad pathway, C16:0 conferred enhanced growth to S. aureus , but not S. epidermidis . Acidic pH and C16 fatty acids stimulated SspA serine protease production in S. aureus but repressed the orthologous Esp protease in S. epidermidis . Although S. aureus biofilm formation was stimulated by acidic pH and C16:0, this effect was abrogated by 25 µM C16:1 which promotes protease production, whereas S. epidermidis maintained enhanced biofilm in presence of C16:1. Exogenous C16:0 was directly incorporated into phospholipid by S. epidermidis but was extended to C18:0 and C20:0 in S. aureus prior to incorporation. This may account for differential signaling through the GraSR two component sensor, which is required for SspA production in S. aureus at acidic pH. Notably, singular graSR dependent phenotypes in S. aureus graS/R deletions were restored by S. epidermidis graS/R at acidic pH alone, whereas growth at pH 5.5 with 25 µM C16:1 could only be restored with S. aureus graS/R . These findings provide important new insight into how members of the Staphylococcal genus are differentially influenced by common environmental signals on human skin. IMPORTANCE Human skin is a chemically hostile environment, with acidic pH and antimicrobial fatty acids that challenge microbial survival. Understanding how closely related Staphylococcus epidermidis and Staphylococcus aureus navigate these conditions is critical for distinguishing commensal behavior from pathogenic potential. Our research reveals that S. aureus and S. epidermidis , though genetically similar, employ markedly distinct adaptive mechanisms in response to identical skin-derived cues. Specifically, each species remodels its membrane phospholipids in unique ways under acidic pH and C16 fatty acid exposure. These environmental factors also differentially modulate their biofilm formation and protease activity. Together, our findings highlight how the same host-derived chemical signals of skin can activate virulence-associated traits in S. aureus while supporting commensal persistence in S. epidermidis .