{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:23:49Z","timestamp":1787750629240,"version":"build-2784847793"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Science & Technology Development Fund of Tianjin Education Commission for Higher Education","award":["2024KJ005"],"award-info":[{"award-number":["2024KJ005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>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-\u03b3 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-\u03b3 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-\u03b3 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-1\u03b2 when combined with an RXR agonist, implying a protective effect on host tissues through PPAR-\u03b3 activation. Conclusions: These findings demonstrate that daidzein and genistein serve as effective adjuncts to conventional antibiotics, exerting multifaceted actions against P. aeruginosa infection.<\/jats:p>","DOI":"10.3390\/antibiotics15090829","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:59:57Z","timestamp":1787749197000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isoflavones with Multifaceted Activities Synergistically Sensitize Pseudomonas aeruginosa to Antibiotics In Vitro and In Vivo"],"prefix":"10.3390","volume":"15","author":[{"given":"Dan-Dan","family":"Li","sequence":"first","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4490-1660","authenticated-orcid":false,"given":"Wen-Xin","family":"Niu","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tie","family":"Yao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Liaoning University, Shenyang 110036, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4290-2945","authenticated-orcid":false,"given":"Joon-Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Li","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. 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