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

Autor: Liu J; Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P. R. China.; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Zhao SY; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Hu JY; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Chen QX; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Jiao SM; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Xiao HC; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Zhang Q; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Xu J; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Zhao JF; Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P. R. China., Zhou HB; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China., Zheng JX; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong 510006, P. R. China., Sun PH; Department of Oncology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P. R. China.; College of Pharmacy, Shihezi University, Shihezi, Xinjiang 832099, P. R. China.; College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, P. R. China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 Nov 09; Vol. 66 (21), pp. 14735-14754. Date of Electronic Publication: 2023 Oct 24.
DOI: 10.1021/acs.jmedchem.3c01268
Abstrakt: 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 (IC 50 = 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.
Databáze: MEDLINE
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