Staphylococcus aureus fatty acid metabolism governs saeRS-mediated aggregation in joint infections.

Staphylococcus aureus can form aggregates within human synovial fluid, contributing to joint infections that are resistant to conventional therapies. However, the regulatory pathways underlying this process remain unclear. Here, we reveal that the S. aureus two-component system saeRS contributes to synovial aggregation by controlling the expression of fibrinectin-binding proteins A and B (FnbA/B), which bind to human fibrinogen and cause aggregation. We further demonstrate that the fatty acid kinase (fak) system is the primary regulator for SaeS activity under host conditions. Mechanistically, fak is epistatic to saeRS by scavenging exogenous fatty acids and altering the localization of SaeS into functional membrane microdomains (FMMs), which are essential for SaeS function. We also identify that undecanoic acid (UDA) is capable of inhibiting the fak pathway, demonstrating its efficacy and potential applicability in treating joint infections. Altogether, these findings highlight the fak-saeRS axis as a potential therapeutic target for joint infections and underscore UDA as a promising treatment for these infections.