Novel Coumarin Derivatives Inhibit the Quorum Sensing System and Iron Homeostasis as Antibacterial Synergists against Pseudomonas aeruginosa.

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is well-known to cause biofilm-associated drug resistance and infections that often lead to treatment failure. Herein, we reported a dual-acting antibiofilm strategy by inhibiting both the bacterial quorum sensing system and the iron uptake system. A series of coumarin derivatives were synthesized and evaluated, and compound 4t was identified as the most effective biofilm inhibitor (IC50 = 3.6 μM). Further mechanistic studies have confirmed that 4t not only inhibits the QS systems but also competes strongly with pyoverdine as an iron chelator, causing an iron deficiency in P. aeruginosa. Additionally, 4t significantly improved the synergistic antibacterial effects of ciprofloxacin and tobramycin by more than 200-1000-fold compared to the single-dose antibiotic treatments. Therefore, our study has shown that 4t is a potentially novel antibacterial synergist candidate to treat bacterial infections.

• Authors: Jun Liu, Si-Yu Zhao, Jia-Yi Hu, Qiu-Xian Chen, Shu-Meng Jiao, Hai-Chuan Xiao, Qiang Zhang, Jun Xu, Jian-Fu Zhao, Hai-Bo Zhou, Jun-Xia Zheng, Ping-Hua Sun
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 21 Pg. 14735-14754 (11 09 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 37874867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coumarins
• Anti-Bacterial Agents
• Iron
• Virulence Factors
• Bacterial Proteins

Topics

• Quorum Sensing
• Pseudomonas aeruginosa
• Coumarins (pharmacology)
• Anti-Bacterial Agents (pharmacology)
• Biofilms
• Iron (pharmacology)
• Homeostasis
• Virulence Factors
• Bacterial Proteins