A microbiome-derived metabolite from Staphylococcus epidermidis inhibits Staphylococcus aureus biofilm formation and virulence

Staphylococcus epidermidis is a common member of the healthy skin microbiome that contributes to barrier function and protection against pathogen colonization. In contrast, Staphylococcus aureus is a major human pathogen and the leading cause of skin and soft tissue infections, owing in part to its robust biofilm-forming capacity and increasing antimicrobial resistance. We previously demonstrated that S. epidermidis cell-free conditioned media (CFCM) inhibit S. aureus biofilm formation by altering bacterial gene expression without affecting growth. Here, we identify the metabolite responsible for this activity. Bioactivity-guided fractionation of S. epidermidis CFCM revealed pyroglutamic acid (PCA) as the active antibiofilm compound. Commercially sourced PCA inhibited S. aureus biofilm formation and reduced adhesion to epithelial cells. In a murine skin infection model, PCA treatment significantly attenuated disease severity, accelerated wound healing, and reduced bacterial burden. Analysis of S. epidermidis CFCM by chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry confirmed the presence of PCA and identified it as the bioactive constituent responsible for antibiofilm activity. Together, these findings uncover a previously unrecognized mechanism by which S. epidermidis suppresses S. aureus virulence and highlight the potential of microbiome-derived metabolites as therapeutics for the prevention and treatment of S. aureus skin infections.