群体感应
铜绿假单胞菌
生物膜
微生物学
毒力
化学
金黄色葡萄球菌
体内
细菌
斑马鱼
抗生素
生物
生物化学
遗传学
生物技术
基因
作者
Jun Liu,Q Chen,Wenfu Wu,Wei Dong,Siyu Zhao,Jia-Hao Li,Yiqun Chang,Shaogao Zeng,Jijie Hu,Yujie Li,Jiaxin Du,Shu‐Meng Jiao,Hai-Chuan Xiao,Qiang Zhang,Jianguo Xu,Jun Zhao,Haibo Zhou,Yong‐Heng Wang,Jian Zou,Pinghua Sun
标识
DOI:10.1016/j.ejmech.2023.115972
摘要
The increasing antibiotic resistance driven by Pseudomonas aeruginosa typically leads to uncontrolled and persistent inflammatory damage, which is primarily attributed to the virulence and biofilms produced by the bacteria. Herein, we present a novel anti-infective drug strategy designed to inhibit the bacterial quorum sensing system, thereby attenuating P. aeruginosa virulence, and modulating inflammation from drug-resistant bacterial infections. We discovered new quorum sensing LasR/LasB inhibitors derived from the structural modification of a ligustilide derivative library. Of these compounds, 5f demonstrated significant inhibitory activity against LasB (LasB-gfp, IC50 = 8.7 μM) and a moderate inhibitory effect on P. aeruginosa biofilms (IC50 = 7.4 μM). Through live image analysis in a fluorescent protein–labeled zebrafish larva model, we observed that compound 5f significantly inhibited the migration of macrophages. Moreover, compound 5f effectively attenuated quorum sensing–mediated virulence factors and biofilm formation by P. aeruginosa. It also alleviated the inflammatory response by P. aeruginosa–infected macrophages through the downregulation of mitogen-activated protein kinase and NF-κB signal-transduction pathways. Notably, in vivo experiments, this compound demonstrated marked therapeutic effects in acute lung injury models induced by lipopolysaccharides from P. aeruginosa. These results indicate that compound 5f has the potential to be a novel anti-infective candidate against drug-resistant infections caused by P. aeruginosa.
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