Developing 3-(2-Isocyano-6-methylbenzyl)-1H-indole Derivatives to Enhance the Susceptibility of Serratia marcescens by Occluding Quorum Sensing,ACS Infectious Diseases

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Developing 3-(2-Isocyano-6-methylbenzyl)-1H-indole Derivatives to Enhance the Susceptibility of Serratia marcescens by Occluding Quorum Sensing
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2023-11-16 , DOI: 10.1021/acsinfecdis.3c00433
Jiang Wang _{1,

2,

3} , Jing-Yi Yang ₁ , Pradeepraj Durairaj ₃ , Wei Wang ₁ , Shi Tang ₁ , Dayong Wang ₁ , Chao-Yun Cai ₃ , Ai-Qun Jia ₂

Affiliation

Quorum sensing (QS) inhibition is recognized as a novel antimicrobial target for infections caused by drug-resistant pathogens and is an attractive strategy for antipathogenic agent development. We designed and synthesized three parts of 3-(2-isocyanobenzyl)-1H-indole derivatives and tested their activity as novel quorum sensing inhibitors (QSIs). 3-(2-Isocyanobenzyl)-1H-indole derivatives demonstrated promising QS, biofilms, and prodigiosin inhibitory activities against Serratia marcescens at subminimum inhibitory concentrations (sub-MICs). In particular, 3-(2-isocyano-6-methylbenzyl)-1H-indole (IMBI, 32) was identified as the best candidate based on several screening assays, including biofilm and prodigiosin inhibition. Further studies demonstrated that exposure to IMBI at 1.56 μg/mL to S. marcescens NJ01 significantly inhibited the formation of biofilms by 42%. The IMBI treatment on S. marcescens NJ01 notably enhanced the susceptibility of the formed biofilms, destroying the architecture of the biofilms by up to 40%, as evidenced by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). For interference of virulence factors in S. marcescens NJ01, IMBI at 3.12 μg/mL inhibited the activity of protease and extracellular polysaccharides (EPS) by 17% and 51%, respectively, which were higher than that of the positive control vanillic acid (VAN). Furthermore, IMBI downregulated the expression of QS- and biofilm-related genes fimA, bsmA, pigP, flhC, rssB, fimC, and rsmA by 1.02- to 2.74-fold. To confirm these findings, molecular docking was performed, which indicated that the binding of IMBI to SmaR, RhlI, RhlR, LasR, and CviR could antagonize the expression of QS-linked traits. In addition, molecular dynamic simulations (MD) and energy calculations indicated that the binding of receptors with IMBI was extremely stable. The biofilms of S. marcescens NJ01 were markedly reduced by 50% when IMBI (0.39 μg/mL) was combined with kanamycin (0.15 μg/mL). In conclusion, this study highlights the potency of IMBI in inhibiting the virulence factors of S. marcescens. IMBI has all the potential to be developed as an effective and efficient QS inhibitor and antibiofilm agent in order to restore or improve antimicrobial drug sensitivity.

中文翻译：

开发 3-(2-异氰基-6-甲基苄基)-1H-吲哚衍生物，通过封闭群体感应增强粘质沙雷氏菌的敏感性

群体感应（QS）抑制被认为是针对耐药病原体引起的感染的新型抗菌靶标，并且是抗病原体药物开发的一个有吸引力的策略。我们设计并合成了三部分 3-(2-异氰基苯甲基)-1 H-吲哚衍生物，并测试了它们作为新型群体感应抑制剂 (QSI) 的活性。 3-(2-异氰基苯甲基)-1 H-吲哚衍生物在亚最低抑制浓度 (亚 MIC) 下对粘质沙雷氏菌表现出有前景的 QS、生物膜和灵菌红抑制活性。特别地，基于包括生物膜和灵菌红素抑制在内的多种筛选测定，3-(2-异氰基-6-甲基苄基)-1H-吲哚(IMBI， 32 )被确定为最佳候选物。进一步的研究表明，粘质沙门氏菌NJ01 暴露于 1.56 μg/mL 的 IMBI 中，可显着抑制 42% 的生物膜形成。扫描电子显微镜 (SEM) 和共焦激光扫描显微镜 (CLSM) 证明，粘质沙门氏菌NJ01 的 IMBI 处理显着增强了形成的生物膜的敏感性，破坏了生物膜的结构高达 40%。对于粘质链球菌NJ01毒力因子的干扰，3.12 μg/mL的IMBI对蛋白酶和胞外多糖（EPS）的活性分别抑制17%和51%，均高于阳性对照香草酸（VAN））。此外，IMBI 将 QS 和生物膜相关基因fimA 、 bsmA 、 pigP 、 flhC 、 rssB 、 fimC和rsmA的表达下调 1.02 至 2.74 倍。为了证实这些发现，进行了分子对接，结果表明 IMBI 与 SmaR、RhlI、RhlR、LasR 和 CviR 的结合可以拮抗 QS 连锁性状的表达。此外，分子动力学模拟（MD）和能量计算表明受体与IMBI的结合极其稳定。当 IMBI (0.39 μg/mL) 与卡那霉素 (0.15 μg/mL) 组合时，粘质链球菌NJ01 的生物膜显着减少 50%。总之，本研究强调了 IMBI 在抑制粘质沙门氏菌毒力因子方面的效力。 IMBI 具有开发为有效且高效的 QS 抑制剂和抗生物膜剂的所有潜力，以恢复或提高抗菌药物敏感性。

更新日期：2023-11-16

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