Wang Jiang, Yang Jing-Yi, Durairaj Pradeepraj, Wen Wei-Huan, Sabapathi Nadana, Yang Liang, Wang Bo, Jia Ai-Qun
Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University Haikou 570311 China
Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University Sanya 572022 China.
RSC Med Chem. 2024 Jul 31;15(9):3256-71. doi: 10.1039/d4md00354c.
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-indole derivatives as novel quorum sensing inhibitors (QSIs). Initial screenings of their QS inhibitory activities were conducted against PAO1 and CV026. Notably, six 3-(2-isocyanobenzyl)-1-indole derivatives (4, 12, 25, 28, 32, and 33) exhibited promising QS, biofilms, and pyocyanin inhibitory activities under minimum inhibitory concentrations (MICs) against PAO1. Among them, 3-(2-isocyano-6-methylbenzyl)-1-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 inhibited biofilm formation by 70% against 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 PAO1, derivative 32 (25 μg mL) 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 also exhibited effective inhibition of swimming and swarming motilities. Moreover, it downregulated the expressions of QS-related genes, including , , , , , , , , and , 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 CCK-8 assay demonstrated low cytotoxicity. Overall, this study underscores the efficacy of derivative 32 in inhibiting virulence factors in . Derivative 32 emerges as a potential QSI for controlling PAO1 infections and an anti-biofilm agent for restoring or enhancing drug sensitivity in drug-resistant pathogens.
群体感应（QS）抑制作为一种对抗耐药病原体引起的感染的创新治疗策略而备受关注。在本研究中，我们评估了3-(2-异氰基苄基)-1-吲哚衍生物作为新型群体感应抑制剂（QSIs）的潜力。针对PAO1和CV026对其QS抑制活性进行了初步筛选。值得注意的是，六种3-(2-异氰基苄基)-1-吲哚衍生物（4、12、25、28、32和33）在对PAO1的最低抑菌浓度（MICs）下表现出有前景的QS、生物膜和绿脓菌素抑制活性。其中，3-(2-异氰基-6-甲基苄基)-1-吲哚（IMBI，32）成为最有前景的候选物，表现出卓越的生物膜和绿脓菌素抑制作用。进一步的综合研究表明，25 μg/mL的衍生物32对PAO1生物膜形成的抑制率达70%，扫描电子显微镜（SEM）证实了这一点。此外，衍生物32显著提高了成熟生物膜的敏感性，导致生物膜结构破坏57%。在干扰PAO1中的毒力因子方面，25 μg/mL的衍生物32对绿脓菌素、蛋白酶和胞外多糖（EPS）分别表现出73%、51%和37%的显著抑制作用，超过阳性对照白藜芦醇（RSV）。25 μg/mL的衍生物32还对游泳和群集运动表现出有效抑制。此外，它下调了QS相关基因（包括、、、、、、、和）的表达1.82至10.87倍。分子对接、分子动力学模拟（MD）和能量计算进一步支持了32与LasR、RhlI、RhlR、EsaL和PqsR的稳定结合，拮抗QS相关性状的表达。通过CCK-8测定评估衍生物32对HEK293T细胞的毒性，结果显示细胞毒性较低。总体而言，本研究强调了衍生物32在抑制PAO1中毒力因子方面的功效。衍生物32成为控制PAO1感染的潜在QSIs以及恢复或增强耐药病原体药物敏感性的抗生物膜剂。
