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

Staphylococcus aureus is the leading global cause of death associated with antimicrobial resistance, driven by its ability to colonize the human nasal cavity and adhere to the keratinized skin epithelium. These colonizers are the primary source of subsequent infections, underscoring the need for decolonization strategies. Using a high-throughput whole cell-based S. aureus adhesion screen, we identified a naturally occurring polyunsaturated branched-chain fatty acid, geranylgeranoic acid (GGA), that inhibits S. aureus adhesion to keratin at concentrations that do not affect cell growth. Mechanistic characterization demonstrated that GGA is a broad-spectrum anti-adhesive compound, inhibiting S. aureus adhesion to keratin, fibronectin, fibrinogen, and immunoglobulins. Structure-activity studies revealed that the carboxylic acid moiety and the presence of one or more double bonds in the carbon chain are key to activity, with various unsaturated fatty acids, including host-derived compounds, showing potent anti-adhesive properties. GGA was found to modulate the production of several S. aureus cell wall-anchored (CWA) proteins; for the fibronectin-binding proteins, this was linked to inhibition of the SaeRS two-component system, impairing S. aureus invasion of endothelial cells. In summary, GGA is a potent, naturally occurring anti-adhesive compound that modulates the production of CWA proteins in S. aureus. Our findings further emphasize the complex role of unsaturated fatty acids in host-pathogen interactions and their potential as S. aureus antivirulence agents. Overall design: (1) RNA-seq analysis of wildtype JE2 Staphylococcus aureus treated and untreated with geranylgeranoic acid (2) RNA-seq analysis of wildtype JE2 Staphylococcus aureus treated and untreated with geranylgeranoic acid at early exponential (OD600nm=0.3), mid-exponential (OD600nm=0.6), early stationary (OD600nm=1.0). (2) RNA-seq analysis of wildtype JE2 Staphylococcus aureus versus JE2-saeS::Tn at the same timepoints as above.