New Pqs Quorum Sensing System Inhibitor as an Antibacterial Synergist against Multidrug-Resistant Pseudomonas aeruginosa

作者：Jun Liu, Jinsong Hou, Yiqun Chang, Lijun Peng, Xiaoyi Zhang, Zhiying Miao, Pinghua Sun, Jing Lin, Wei‐Min Chen · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c01781 · 被引用次数：63 · 研究领域：Bacterial biofilms and quorum sensing、Antibiotic Resistance in Bacteria、Antimicrobial Peptides and Activities

Development of new bacterial biofilm inhibitors as antibacterial synergists is an effective strategy to solve the resistance of Pseudomonas aeruginosa . In this paper, a series of 3-hydroxy-pyridin-4(1 H )-ones were synthesized and evaluated, and the hit compound ( 20p ) was identified with the effects of inhibiting the production of pyocyanin (IC 50 = 8.6 μM) and biofilm formation (IC 50 = 4.5 μM). Mechanistic studies confirmed that 20p inhibits the formation of bacterial biofilm by inhibiting the expression of pqsA, blocking pqs quorum sensing system quinolone biosynthesis. Moreover, we systematically investigated the bactericidal effects of combining currently approved antibiotics for CF including tobramycin, ciprofloxacin, and colistin E with 20p, which showed obvious antibacterial synergy to overcome antibiotics resistance in multidrug-resistant P. aeruginosa biofilms. The result indicates that compound 20p may be used in the future as a potentially novel antibacterial synergist candidate for the treatment of P. aeruginosa infections.