The Oxylipin Dependent Quorum Sensing System enhances Pseudomonas aeruginosa dissemination during burn-associated infection.

Pseudomonas aeruginosa is a leading cause of life-threatening infections in burn patients, yet the molecular cues driving its hypervirulence remain poorly understood. Here, we identify the Oxylipin Dependent Quorum Sensing (ODS) system as a key regulator of P. aeruginosa pathogenicity in the burn wound environment. Using a murine burn model, we show that thermal injury significantly increases free oleic acid levels in skin, which P. aeruginosa converts into oxylipin autoinducers (10-HOME and 7,10-DiHOME) via OdsA and OdsB. These molecules activate the ODS regulon, promoting bacterial invasion of burned tissue and dissemination to internal organs. ODS-deficient mutants exhibited markedly reduced skin colonization, impaired translocation across endothelial barriers, and attenuated mortality compared to wild-type strains, confirming the role of ODS in hypervirulence. Importantly, immunization with recombinant OdsA or treatment with a small-molecule OdsA inhibitor significantly improved survival and reduced bacterial dissemination in burned mice. High-throughput screening identified AB012 as a potent OdsA inhibitor, which competitively binds the enzyme's catalytic site and suppresses oxylipin synthesis, ODS gene expression, and biofilm formation without affecting bacterial growth. In vivo, AB012 reduced bacterial burden and systemic spread following burn injury. Collectively, these findings reveal that P. aeruginosa exploits host-derived oleic acid to activate ODS and enhance virulence, and they highlight OdsA as a promising target for therapeutic intervention to prevent sepsis in burn patients.