结核菌呼吸链细胞色素bd氧化酶（Cyt-bd）抑制剂的设计、合成与生物活性研究

耐药结核菌导致结核病的临床治疗效果不佳，临床迫切需求新型作用机制的抗结核菌药物。结核菌能量呼吸链中的细胞色素bcc氧化酶（Cyt-bcc）成为抗结核药物研究的有效靶标。然而最新研究揭示：细胞色素bd氧化酶（Cyt-bd）在Cyt-bcc被抑制的情况下成为能量传递的代偿路径，导致Cyt-bcc抑制剂单药治疗效果下降。由此推测：同时抑制Cyt-bcc和Cyt-bd成为治疗耐药结核菌的一种新策略。但目前尚无Cyt-bd有效抑制剂的报道。前期通过虚拟筛选，已获得了作用于Cyt-bd抑制剂先导化合物L1,对Cyt-bd的结合常数Kd为0.6μM，对敲除Cyt-bcc结核菌抑制活性MIC为3.12μM。本项目将在先导物L1的基础上，结合抗结核优势骨架片段，进行全面的结构优化，构效关系以及体外抗结核活性研究，进一步提高其活性，为临床抗结核药物研究提供具有全新作用机制的先导化合物。

Drug-resistant Mycobacterium tuberculosis (Mtb) lead to poor clinical treatment of tuberculosis, and there is an urgent clinical need for anti-tuberculosis drugs with new mechanisms of action. Cytochrome bcc oxidase (Cyt-bcc) in the energy respiratory chain of tuberculosis bacteria has become an effective target for anti-tuberculosis drug research. However, the latest research reveals that cytochrome bd oxidase (Cyt-bd) becomes a compensatory for the energy respiratory chain when Cyt-bcc is inhibited, resulting in a decrease in the efficacy of Cyt-bcc inhibitor monotherapy. It is speculated from this that simultaneous inhibition of Cyt-bcc and Cyt-bd a new strategy for the treatment of drug-resistant Mtb. However, there are no reports of effective inhibitors of Cyt-bd. Through virtual screening, we obtained the lead compound L1 that acts on the Cyt-bd with the binding constant Kd 0.6 μM, and the MIC against Mtb is 3.12 μM. Based on the lead L1, this project will conduct comprehensive structural optimization, structure-activity relationship and in vitro anti-tuberculosis activity studies based on the lead L1, combined with anti-tuberculosis superior skeleton fragments, to further improve its activity and provide a new mechanism of action for clinical anti-tuberculosis drug research.