Discovery and evaluation of 3-(2-isocyanobenzyl)-1H-indole derivatives as potential quorum sensing inhibitors for the control of Pseudomonas aeruginosa infections in vitro†

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jiang Wang, Jing-Yi Yang, Pradeepraj Durairaj, Wei-Huan Wen, Nadana Sabapathi, Liang Yang, Bo Wang and Ai-Qun Jia
{"title":"Discovery and evaluation of 3-(2-isocyanobenzyl)-1H-indole derivatives as potential quorum sensing inhibitors for the control of Pseudomonas aeruginosa infections in vitro†","authors":"Jiang Wang, Jing-Yi Yang, Pradeepraj Durairaj, Wei-Huan Wen, Nadana Sabapathi, Liang Yang, Bo Wang and Ai-Qun Jia","doi":"10.1039/D4MD00354C","DOIUrl":null,"url":null,"abstract":"<p >Quorum sensing (QS) inhibition stands out as an innovative therapeutic strategy for combating infections caused by drug-resistant pathogens. In this study, we assessed the potential of 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against <em>Pseudomonas aeruginosa</em> PAO1 and <em>Chromobacterium violaceum</em> CV026. Notably, six 3-(2-isocyanobenzyl)-1<em>H</em>-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against <em>P. aeruginosa</em> PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1<em>H</em>-indole (IMBI, 32) emerged as the most promising candidate, demonstrating superior biofilm and pyocyanin inhibition. Further comprehensive studies revealed that derivative 32 at 25 μg mL<small><sup>−1</sup></small> inhibited biofilm formation by 70% against <em>P. aeruginosa</em> PAO1, as confirmed by scanning electron microscopy (SEM). Additionally, derivative 32 substantially increased the susceptibility of mature biofilms, leading to a 57% destruction of biofilm architecture. In terms of interfering with virulence factors in <em>P. aeruginosa</em> PAO1, derivative 32 (25 μg mL<small><sup>−1</sup></small>) displayed remarkable inhibitory effects on pyocyanin, protease, and extracellular polysaccharides (EPS) by 73%, 51%, and 37%, respectively, exceeding the positive control resveratrol (RSV). Derivative 32 at 25 μg mL<small><sup>−1</sup></small> also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including <em>lasI</em>, <em>lasR</em>, <em>rhlI</em>, <em>rhlR</em>, <em>pqsR</em>, <em>sdhB</em>, <em>sucD</em>, <em>sodB</em>, and <em>PA5439</em>, by 1.82- to 10.87-fold. Molecular docking, molecular dynamics simulations (MD), and energy calculations further supported the stable binding of 32 to LasR, RhlI, RhlR, EsaL, and PqsR antagonizing the expression of QS-linked traits. Evaluation of the toxicity of derivative 32 on HEK293T cells <em>via</em> CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in <em>P. aeruginosa</em>. Derivative 32 emerges as a potential QSI for controlling <em>P. aeruginosa</em> PAO1 infections <em>in vitro</em> and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 9","pages":" 3256-3271"},"PeriodicalIF":4.1000,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2024/md/d4md00354c","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Quorum sensing (QS) inhibition stands out as an innovative therapeutic strategy for combating infections caused by drug-resistant pathogens. In this study, we assessed the potential of 3-(2-isocyanobenzyl)-1H-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against Pseudomonas aeruginosa PAO1 and Chromobacterium violaceum CV026. Notably, six 3-(2-isocyanobenzyl)-1H-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against P. aeruginosa PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1H-indole (IMBI, 32) emerged as the most promising candidate, demonstrating superior biofilm and pyocyanin inhibition. Further comprehensive studies revealed that derivative 32 at 25 μg mL−1 inhibited biofilm formation by 70% against P. aeruginosa PAO1, as confirmed by scanning electron microscopy (SEM). Additionally, derivative 32 substantially increased the susceptibility of mature biofilms, leading to a 57% destruction of biofilm architecture. In terms of interfering with virulence factors in P. aeruginosa PAO1, derivative 32 (25 μg mL−1) displayed remarkable inhibitory effects on pyocyanin, protease, and extracellular polysaccharides (EPS) by 73%, 51%, and 37%, respectively, exceeding the positive control resveratrol (RSV). Derivative 32 at 25 μg mL−1 also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including lasI, lasR, rhlI, rhlR, pqsR, sdhB, sucD, sodB, and PA5439, by 1.82- to 10.87-fold. Molecular docking, molecular dynamics simulations (MD), and energy calculations further supported the stable binding of 32 to LasR, RhlI, RhlR, EsaL, and PqsR antagonizing the expression of QS-linked traits. Evaluation of the toxicity of derivative 32 on HEK293T cells via CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in P. aeruginosa. Derivative 32 emerges as a potential QSI for controlling P. aeruginosa PAO1 infections in vitro and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.

Abstract Image

Abstract Image

发现和评估 3-(2-异氰基苄基)-1H-吲哚衍生物作为潜在的法定人数感应抑制剂,用于控制铜绿假单胞菌体外感染。
抑制法定人数感应(QS)是对抗耐药病原体感染的一种创新治疗策略。在这项研究中,我们评估了 3-(2-异氰基苄基)-1H-吲哚衍生物作为新型法定量感应抑制剂(QSIs)的潜力。我们初步筛选了这些衍生物对铜绿假单胞菌 PAO1 和奇异变形杆菌 CV026 的 QS 抑制活性。值得注意的是,六种 3-(2-异氰基苄基)-1H-吲哚衍生物(4、12、25、28、32 和 33)在最低抑菌浓度(MICs)下对铜绿假单胞菌 PAO1 具有良好的 QS、生物膜和脓青素抑制活性。其中,3-(2-异氰基-6-甲基苄基)-1H-吲哚(IMBI,32)是最有希望的候选化合物,表现出卓越的生物膜和脓蓝蛋白抑制能力。进一步的综合研究显示,经扫描电子显微镜(SEM)证实,25 μg mL-1 的衍生物 32 对铜绿假单胞菌 PAO1 的生物膜形成抑制率为 70%。此外,衍生物 32 还大大增加了成熟生物膜的敏感性,使生物膜结构的破坏率达到 57%。在干扰铜绿假单胞菌 PAO1 的毒力因子方面,衍生物 32(25 μg mL-1)对脓青素、蛋白酶和细胞外多糖(EPS)的抑制效果显著,分别超过阳性对照白藜芦醇(RSV)73%、51% 和 37%。25 μg mL-1 的衍生物 32 还能有效抑制游动和成群运动。此外,它还下调了 QS 相关基因的表达,包括 lasI、lasR、rhlI、rhlR、pqsR、sdhB、sucD、sodB 和 PA5439,下调幅度为 1.82-10.87 倍。分子对接、分子动力学模拟(MD)和能量计算进一步证实了 32 与 LasR、RhlI、RhlR、EsaL 和 PqsR 的稳定结合可拮抗 QS 链接性状的表达。通过 CCK-8 试验评估了 32 号衍生物对 HEK293T 细胞的毒性,结果显示其细胞毒性较低。总之,这项研究强调了 32 号衍生物在抑制铜绿假单胞菌毒力因子方面的功效。衍生物 32 是一种潜在的 QSI,可用于控制铜绿假单胞菌 PAO1 的体外感染,也是一种抗生物膜剂,可用于恢复或增强耐药病原体对药物的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信