Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, 610106, China.
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, 610106, China; Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China.
Microb Pathog. 2024 Nov;196:107010. doi: 10.1016/j.micpath.2024.107010. Epub 2024 Oct 11.
The quorum-sensing (QS) system of Pseudomonas aeruginosa dominates the pathogenicity of the acute or chronic infection process. Hence, curbing the pathogenicity of P. aeruginosa by targeting QS system is an ideal strategy. This study aims to identify potential anti-virulence compounds that can effectively disrupt the QS system of P. aeruginosa using a combination of virtual screening and experimental validation techniques. We explored inhibitory effect of isovanillin obtained by virtual screening on P. aeruginosa QS regulated virulence factors extracellular protease, biofilm, and pyocyanin. Results displayed that isovanillin could inhibit the virulence phenotypes regulated by the las- and pqs-QS systems of P. aeruginosa. The synthesis of extracellular proteases, pyocyanin, and biofilm formation by P. aeruginosa were dramatically inhibited by sub-MICs doses of isovanillin. The results of RNA sequencing and quantitative PCR revealed that the QS-activated genes down-regulated by subinhibitory isovanillin in the transcriptional evels. Furthermore, the presence of isovanillin increased the susceptibility of drug-resistant P. aeruginosa to kanamycin, meropenem, and polymyxin B. Treatment of isovanillin as a monotherapy significantly decreased the mortality of C. elegans in P. aeruginosa PAO1 or UCBPP-PA14 (PA14) infection. Our study reported the anti-virulence activity of isovanillin against P. aeruginosa, and provided a structural foundation for developing anti-virulence drugs targeting the QS system of P. aeruginosa.
铜绿假单胞菌的群体感应（QS）系统主导着急性或慢性感染过程的致病性。因此，通过靶向 QS 系统来抑制铜绿假单胞菌的致病性是一种理想的策略。本研究旨在使用虚拟筛选和实验验证技术的组合，鉴定能够有效破坏铜绿假单胞菌 QS 系统的潜在抗毒化合物。我们探索了通过虚拟筛选获得的异香草醛对铜绿假单胞菌 QS 调节的毒力因子细胞外蛋白酶、生物膜和绿脓菌素的抑制作用。结果表明，异香草醛可抑制铜绿假单胞菌 las 和 pqs-QS 系统调节的毒力表型。亚最低抑菌浓度剂量的异香草醛可显著抑制铜绿假单胞菌细胞外蛋白酶、绿脓菌素和生物膜形成。RNA 测序和定量 PCR 的结果表明，亚抑制浓度的异香草醛在转录水平下调了 QS 激活的基因。此外，异香草醛的存在增加了耐多药铜绿假单胞菌对卡那霉素、美罗培南和多粘菌素 B 的敏感性。异香草醛单药治疗可显著降低铜绿假单胞菌 PAO1 或 UCBPP-PA14（PA14）感染的秀丽隐杆线虫的死亡率。本研究报道了异香草醛对铜绿假单胞菌的抗毒力活性，为开发针对铜绿假单胞菌 QS 系统的抗毒力药物提供了结构基础。
