Discovery of β-nitrostyrene derivatives as potential quorum sensing inhibitors for biofilm inhibition and antivirulence factor therapeutics against Serratia marcescens.

IF 4.5 Q1 MICROBIOLOGY mLife Pub Date : 2024-09-06 eCollection Date: 2024-09-01 DOI:10.1002/mlf2.12135
Jiang Wang, Jingyi Yang, Pradeepraj Durairaj, Wei Wang, Dongyan Wei, Shi Tang, Haiqing Liu, Dayong Wang, Ai-Qun Jia
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Abstract

Quorum sensing (QS) inhibition has emerged as a promising target for directed drug design, providing an appealing strategy for developing antimicrobials, particularly against infections caused by drug-resistant pathogens. In this study, we designed and synthesized a total of 33 β-nitrostyrene derivatives using 1-nitro-2-phenylethane (NPe) as the lead compound, to target the facultative anaerobic bacterial pathogen Serratia marcescens. The QS-inhibitory effects of these compounds were evaluated using S. marcescens NJ01 and the reporter strain Chromobacterium violaceum CV026. Among the 33 new β-nitrostyrene derivatives, (E)-1-methyl-4-(2-nitrovinyl)benzene (m-NPe, compound 28) was proven to be a potent inhibitor that reduced biofilm formation of S. marcescens NJ01 by 79%. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) results revealed that treatment with m-NPe (50 μg/ml) not only enhanced the susceptibility of the formed biofilms but also disrupted the architecture of biofilms by 84%. m-NPe (50 μg/ml) decreased virulence factors in S. marcescens NJ01, reducing the activity of protease, prodigiosin, and extracellular polysaccharide (EPS) by 36%, 72%, and 52%, respectively. In S. marcescens 4547, the activities of hemolysin and EPS were reduced by 28% and 40%, respectively, outperforming the positive control, vanillic acid (VAN). The study also found that the expression levels of QS- and biofilm-related genes (flhD, fimA, fimC, sodB, bsmB, pigA, pigC, and shlA) were downregulated by 1.21- to 2.32-fold. Molecular dynamics analysis showed that m-NPe could bind stably to SmaR, RhlI, RhlR, LasR, and CviR proteins in a 0.1 M sodium chloride solution. Importantly, a microscale thermophoresis (MST) test revealed that SmaR could be a target protein for the screening of a quorum sensing inhibitor (QSI) against S. marcescens. Overall, this study highlights the efficacy of m-NPe in suppressing the virulence factors of S. marcescens, identifying it as a new potential QSI and antibiofilm agent capable of restoring or improving antimicrobial drug sensitivity.

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发现β-硝基苯芘衍生物作为潜在的法定人数感应抑制剂,用于抑制生物膜和抗病毒因子治疗大肠沙雷氏菌。
抑制法定量感应(QS)已成为定向药物设计的一个有前途的靶点,为开发抗菌药物,尤其是抗耐药性病原体引起的感染提供了一种有吸引力的策略。在这项研究中,我们以 1-硝基-2-苯基乙烷(NPe)为先导化合物,针对兼性厌氧细菌病原体 Serratia marcescens,设计并合成了 33 种 β-硝基苯乙烯衍生物。使用 S. marcescens NJ01 和报告菌株 Chromobacterium violaceum CV026 评估了这些化合物的 QS 抑制作用。在 33 种新的β-硝基苯乙烯衍生物中,(E)-1-甲基-4-(2-硝基乙烯基)苯(m-NPe,化合物 28)被证明是一种有效的抑制剂,可将 S. marcescens NJ01 的生物膜形成减少 79%。扫描电子显微镜(SEM)和激光共聚焦扫描显微镜(CLSM)结果表明,用 m-NPe(50 μg/ml)处理不仅提高了已形成生物膜的易感性,而且还破坏了生物膜的结构,破坏率达 84%。m-NPe (50 μg/ml)可减少 S. marcescens NJ01 的毒力因子,使蛋白酶、原肌苷和胞外多糖(EPS)的活性分别降低 36%、72% 和 52%。在 S. marcescens 4547 中,溶血素和 EPS 的活性分别降低了 28% 和 40%,优于阳性对照香草酸(VAN)。研究还发现,QS 和生物膜相关基因(flhD、fimA、fimC、sodB、bsmB、pigA、pigC 和 shlA)的表达水平下调了 1.21-2.32 倍。分子动力学分析表明,在 0.1 M 氯化钠溶液中,m-NPe 可与 SmaR、RhlI、RhlR、LasR 和 CviR 蛋白稳定结合。重要的是,微尺度热泳(MST)测试表明,SmaR 可以作为筛选针对 S. marcescens 的法定量感应抑制剂(QSI)的目标蛋白。总之,本研究强调了 m-NPe 在抑制 S. marcescens 毒力因子方面的功效,将其确定为一种新的潜在 QSI 和抗生物膜剂,能够恢复或提高抗菌药物的敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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