Background/Objectives: Pseudomonas aeruginosa is a notorious multidrug-resistant pathogen that causes serious acute and chronic infections by employing quorum sensing (QS)-regulated virulence, biofilm formation, and host-damaging inflammation. To overcome the yield limitation of two previously identified marine secondary metabolites with dual QS inhibitory and PPAR-γ agonistic activities, we further screened marine-derived natural products for more abundant candidates with similar anti-virulence and anti-inflammatory properties. Methods: In this study, isoflavones were evaluated for anti-QS and PPAR-γ transactivation activities using reporter gene assays, and for antibacterial, anti-virulence, and anti-inflammatory effects via broth microdilution, biofilm, G. mellonella infection, and ELISA cytokine assays. Results: Daidzein and genistein were selected for their optimal anti-QS and PPAR-γ activation activities. They inhibited a key QS regulator and suppressed pyocyanin production and biofilm formation in P. aeruginosa without affecting bacterial growth, indicating minimal selective pressure for resistance. In addition, daidzein and genistein were found to synergistically sensitize the wild-type P. aeruginosa strain to gentamicin, carbenicillin, tobramycin, ampicillin, and polymyxin B, and synergistically or partially synergistically sensitize a multidrug-resistant strain to gentamicin, tobramycin, and ampicillin. Moreover, a Galleria mellonella infection model confirmed that daidzein and genistein significantly enhance the efficacy of gentamicin against P. aeruginosa infection in vivo. Furthermore, in host macrophages, daidzein and genistein significantly inhibited LPS-induced production of NO, IL-6, and IL-1β when combined with an RXR agonist, implying a protective effect on host tissues through PPAR-γ activation. Conclusions: These findings demonstrate that daidzein and genistein serve as effective adjuncts to conventional antibiotics, exerting multifaceted actions against P. aeruginosa infection.

Background/Objectives: Antibiotic resistance is a growing global health challenge, especially with tricky bacteria like Pseudomonas aeruginosa. Anthranilate, previously identified as a signaling molecule in P. aeruginosa, modulates various pathogenicity-related phenotypes by reducing virulence factor production, inhibiting biofilm formation, and increasing antibiotic susceptibility. Based on these good properties as an anti-virulence agent, this study evaluated the actual therapeutic potential of anthranilate using mouse skin infection and lung infection models. Specifically, the efficacy of anthranilate in a standalone treatment was investigated without reliance on conventional antibiotics. Methods: The therapeutic efficacy of anthranilate was evaluated in murine skin and lung infection models of P. aeruginosa. Anthranilate was administered as a standalone treatment, and its effects on bacterial burden, inflammatory responses, and tissue lesion progression were assessed and compared with those of gentamicin treatment. Results: Anthranilate effectively reduced bacterial suppuration, mitigated inflammatory responses, and suppressed lesion progression in infected skin and lung tissues. Notably, anthranilate alone produced therapeutic effects comparable to those of gentamicin. Conclusions: These findings highlight its potential of standalone treatment as an alternative to traditional antibiotics and offer a novel anti-virulence strategy that minimizes selective pressure for resistance development.

The global escalation of antibiotic resistance has profoundly limited the effectiveness of conventional antimicrobial therapies [1]. This challenge is particularly acute for opportunistic pathogens...