An anti-adhesive compound modulating the production of Staphylococcus aureus cell wall-anchored proteins.

As one of the leading global causes of death associated with antimicrobial resistance, Staphylococcus aureus frequently colonizes the human nasal cavity and adheres to keratinized skin, establishing reservoirs that drive subsequent infections and emphasize the need for new decolonization strategies. Using a high-throughput, whole-cell screening platform, here we identify geranylgeranoic acid (GGA), a naturally occurring polyunsaturated, branched-chain fatty acid, as having dual activity against methicillin-resistant S. aureus (MRSA). At elevated concentrations, GGA exhibits microbicidal effects, whereas at sub‑microbicidal doses, it effectively inhibits MRSA adhesion to keratin, fibronectin, fibrinogen, and immunoglobulins. GGA possesses anti-adhesive activity against a panel of multidrug-resistant S. aureus clinical isolates and demonstrates efficacy against MRSA skin and soft tissue infections in mice, offering a promising new avenue for combating this challenging pathogen. The anti-adhesive activity of GGA is attributed to the transcriptional modulation of S. aureus cell wall-anchored (CWA) proteins. For the fibronectin-binding proteins, this effect is mediated by inhibition of the SaeRS two-component system, which, in turn, down-regulates a variety of S. aureus virulence determinants. Our data also suggest that GGA targets additional transcriptional regulators beyond SaeRS. These insights expand the translational relevance of our findings and underscore the potential of GGA as an anti‑MRSA therapeutic.