title: Genetics-directed drug discovery for combating Mycobacterium tuberculosis infection.
abstract: Mycobacterium tuberculosis (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.
authors.affiliation: a Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Quan
authors.affiliation: a Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , P.R. China.
authors.forename: Le
authors.initials: L
authors.lastname: Xiong
authors.affiliation: a Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: a Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics , Huazhong Agricultural University , Wuhan 430070 , P.R. China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Zhang
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D055808:Drug Discovery; D024881:Drug Resistance, Bacterial; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D000071184:Pharmacogenomic Variants; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins
keywords: connectivity map; drug discovery; medical genetics; target; tuberculosis