A quorum sensing antagonist with dual bacterium- and host-directed anti-pathogenic activity against <i>Pseudomonas aeruginosa</i>

Pseudomonas aeruginosa is a major opportunistic pathogen whose clinical management is increasingly compromised by antibiotic resistance and biofilm-associated persistence. Anti-pathogenic strategies that attenuate virulence without inhibiting bacterial growth offer a promising alternative to conventional antibiotics. Here, we identify the Spongosorites sp-derived bisindole alkaloid (R)-6’-debromohamacanthin B (RDB) as a potent dual bacterium- and host-directed anti-pathogenic agent against P. aeruginosa. RDB suppressed quorum sensing (QS) activity and markedly inhibited biofilm formation at growth-independent concentrations starting at 100 pM. Mechanistically, RDB functionally interfered with several central QS regulators, including LasR, RhlR, PqsR, and QscR, consistent with network-level attenuation of QS signaling, and reduced intracellular c-di-GMP levels associated with biofilm regulation. Beyond its bacterium-directed activity, RDB enhanced macrophage-mediated phagocytosis and intracellular bacterial clearance while limiting excessive production of pro-inflammatory mediators. In a murine wound infection model, RDB significantly reduced infection severity, restricted systemic dissemination, and promoted wound healing without detectable toxicity. Collectively, these findings demonstrate that RDB exerts dual bacterium-directed and host-directed activities, simultaneously attenuating virulence and biofilm formation while reinforcing host defense and controlling pathological inflammation. This multifaceted mode of action positions RDB as a promising anti-pathogenic therapeutic candidate for the management of P. aeruginosa infections without promoting antimicrobial resistance.