2. Academic Validation
  3. Design, synthesis and biological evaluation of novel coumarin derivatives as Pseudomonas aeruginosa biofilm inhibitors

Design, synthesis and biological evaluation of novel coumarin derivatives as Pseudomonas aeruginosa biofilm inhibitors

  • Eur J Med Chem. 2026 Jan 15;302(Pt 1):118294. doi: 10.1016/j.ejmech.2025.118294.
Wenqian Liu 1,  Siyu Zhao 2,  Tiantian Xie 1,  Zhenmeng Zhang 2,  Ziyang Du 2,  Pinghua Sun 2,  Feng Huang 3,  Jun Liu 4,  Yun Sun 5
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming, 650500, PR China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632, PR China.
  • 3 School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming, 650500, PR China. Electronic address: [email protected].
  • 4 State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Institute for Advanced and Applied Chemical Synthesis, Jinan University, Guangzhou, 510632, PR China. Electronic address: [email protected].
  • 5 School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming, 650500, PR China. Electronic address: [email protected].
PMID: 41172648 DOI: 10.1016/j.ejmech.2025.118294
Abstract

Biofilm-associated Antibiotic resistance in Pseudomonas aeruginosa (P. aeruginosa) poses a critical global health burden. A promising strategy to deal with resistant P. aeruginosa infections is to interfere with biofilm formation and the production of virulence. In this study, we designed and synthesized a series of novel coumarin derivatives by incorporating long alkyl chains from native QS signal molecules into the coumarin scaffold. Compound XDS-23 emerged as the hit compound with an IC50 of 1.26 ± 0.16 μM to inhibit biofilm in P. aeruginosa PAO1. Furthermore, XDS-23 still exhibited significant efficacy in reducing biofilm and virulence in clinically isolated resistant P. aeruginosa. Mechanistic studies revealed that XDS-23 mainly inhibited the las and pqs systems, thereby suppressing biofilm and multiple virulence factors. Notably, XDS-23 demonstrated synergistic activity with polymyxin B, ciprofloxacin, ceftazidime, and tobramycin against P. aeruginosa both in vitro and in vivo, significantly increasing the survival rate of Galleria mellonella when combined with these Antibiotics. Collectively, these findings highlight biofilm inhibitor XDS-23 as a promising biofilm inhibitor to combat resistant P. aeruginosa infections.

Keywords

Biofilm inhibitor; Pseudomonas aeruginosa; Quorum sensing; Resistance; Virulence.

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