Identification of TonB-dependent siderophore receptor inhibitors against Flavobacterium columnare using a structure-based high-throughput virtual screening method

Minghao Li, Baipeng Chen, Ming Xu, Fulong Li, Yi Geng, Defang Chen, Ouyang Ping, Xiaoli Huang, Yongqiang Deng
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Abstract

TonB-dependent siderophore receptors play a critical transport role for Flavobacterium columnare virulence formation and growth, and have become valuable targets for the development of novel antimicrobial agents. Traditional Chinese medicine has demonstrated notable efficacy in the treatment of fish diseases and includes potential antibacterial agents. Herein, we performed molecular docking-based virtual screening to discover novel TonB-dependent siderophore receptor inhibitors from traditional Chinese medicine and provide information for developing novel antibacterial agents. Firstly, we efficiently obtained 11 potential inhibitors with desirable drug-like characteristics from thousands of compounds in the TCM library based on virtual screening and property prediction. The antibacterial activity of Enoxolone, along with its interaction characteristics, were determined via an MIC assay and molecular dynamic simulation. Transcriptional profiling, along with validation experiments, subsequently revealed that an insufficient uptake of iron ions by bacteria upon binding to the TonB-dependent siderophore receptors is the antibacterial mechanism of Enoxolone. Finally, Enoxolone's acceptable toxicity was illustrated through immersion experiments. In summary, we have used virtual screening techniques for the first time in the development of antimicrobial agents in aquaculture. Through this process, we have identified Enoxolone as a promising compound targeting the TonB-dependent siderophore receptor of F. columnare. In addition, our findings will provide new ideas for the advancement of innovative antimicrobial medications in aquaculture.
利用基于结构的高通量虚拟筛选方法鉴定针对柱状黄杆菌的 TonB 依赖性苷酸受体抑制剂
依赖于 TonB 的苷元受体对黄杆菌的毒力形成和生长起着关键的运输作用,已成为开发新型抗菌剂的重要靶标。中药在治疗鱼病方面具有显著疗效,其中包括潜在的抗菌剂。在此,我们进行了基于分子对接的虚拟筛选,从中药中发现了新型的TonB依赖性苷元受体抑制剂,为开发新型抗菌剂提供了信息。首先,基于虚拟筛选和性质预测,我们从数千个中药化合物库中有效地获得了11个具有理想类药物特征的潜在抑制剂。通过 MIC 试验和分子动力学模拟确定了依诺昔隆的抗菌活性及其相互作用特征。转录谱分析和验证实验随后揭示了依诺昔隆的抗菌机制,即与依赖于TonB的嗜苷受体结合后,细菌对铁离子的吸收不足。最后,通过浸泡实验证明了依诺酮具有可接受的毒性。总之,我们首次将虚拟筛选技术用于水产养殖抗菌剂的开发。通过这一过程,我们发现 Enoxolone 是一种针对 F. columnare 的 TonB 依赖性嗜苷受体的有前途的化合物。此外,我们的研究结果还将为水产养殖中创新抗菌药物的开发提供新思路。
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