Genetics-directed drug discovery for combating <i>Mycobacterium tuberculosis</i> infection

<i>Mycobacterium tuberculosis</i> (Mtb), the pathogen of tuberculosis (TB), is one of the most infectious bacteria in the world. The traditional strategy to combat TB involves targeting the pathogen directly; however, the rapid evolution of drug resistance lessens the efficiency of this anti-TB method. Therefore, in recent years, some researchers have turned to an alternative anti-TB strategy, which hinders Mtb infection through targeting host genes. In this work, using a theoretical genetic analysis, we identified 170 Mtb infection-associated genes from human genetic variations related to Mtb infection. Then, the agents targeting these genes were identified to have high potential as anti-TB drugs. In particular, the agents that can target multiple Mtb infection-associated genes are more druggable than the single-target counterparts. These potential anti-TB agents were further screened by gene expression data derived from connectivity map. As a result, some agents were revealed to have high interest for experimental evaluation. This study not only has important implications for anti-TB drug discovery, but also provides inspirations for streamlining the pipeline of modern drug discovery.结核分枝杆菌（Mycobacterium tuberculosis，缩写Mtb）是结核病（Tuberculosis，缩写TB）的病原菌，也是全球传染性最强的细菌之一。传统抗结核治疗策略以直接靶向该病原菌为主，但耐药性的快速进化大幅削弱了这类抗结核手段的有效性。因此近年来，诸多研究者转向了新型抗结核策略：通过靶向宿主基因阻断结核分枝杆菌的感染过程。本研究通过理论遗传学分析，从与结核分枝杆菌感染相关的人类遗传变异中，鉴定出170个结核分枝杆菌感染相关宿主基因。随后，靶向这些基因的药物被证实具备极高的抗结核药物开发潜力；其中，可同时靶向多个结核分枝杆菌感染相关基因的药物，相较于单靶点药物，具有更优的成药性。研究团队进一步通过连接图谱（Connectivity Map）的基因表达数据，对上述潜在抗结核药物开展了筛选，最终发现了若干值得开展实验验证的候选化合物。本研究不仅对抗结核药物研发具有重要的指导价值，同时也为优化现代药物研发管线提供了全新的思路。