New Pqs Quorum Sensing System Inhibitor as an Antibacterial Synergist against Multidrug-Resistant Pseudomonas aeruginosa
New Pqs Quorum Sensing System Inhibitor as an Antibacterial Synergist against Multidrug-Resistant Pseudomonas aeruginosa
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DOI：
10.1021/acs.jmedchem.1c01781
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发表时间：
2021-12-24
影响因子：
7.3
通讯作者：
Chen, Wei-Min
中科院分区：
文献类型：
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作者：
Liu, Jun;Hou, Jin-Song;Chen, Wei-Min
开发新型细菌生物膜抑制剂作为抗菌增效剂是解决铜绿假单胞菌耐药的有效策略。本文合成了一系列3-羟基吡啶-4(1H)- 1，并对其进行了评价，鉴定出hit化合物（20p）具有抑制花青素生成（IC50 = 8.6 μ M）和生物膜形成（IC50 = 4.5 μ M）的作用。机制研究证实，20p通过抑制pqsA的表达，阻断pqs群体感应系统喹诺酮类药物的生物合成，从而抑制细菌生物膜的形成。此外，我们系统研究了妥布霉素、环丙沙星、粘菌素E等目前已获批的CF抗生素与20p联合使用的杀菌效果，发现20p对耐多药铜绿假单胞菌生物膜的耐药表现出明显的抗菌协同作用。结果表明，化合物20p可能作为一种潜在的新型抗菌增效剂用于治疗铜绿假单胞菌感染。
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(1H)-ones were synthesized and evaluated, and the hit compound (20p) was identified with the effects of inhibiting the production of pyocyanin (IC50 = 8.6 mu M) and biofilm formation (IC50 = 4.5 mu M). 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.