title: A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis.
abstract: Drug resistance in Mycobacterium tuberculosis (Mtb) is caused by mutations in restricted regions of the genome. Mutations in katG, the promoter region of the mabA-inhA operon, and inhA are those most frequently responsible for isoniazid (INH) resistance. Several INH-resistant (INH(r) ) Mtb clinical isolates without mutations in these regions have been described, however, indicating that there are as yet undetermined mechanisms of INH resistance. We identified the mabA(g609a) silent mutation in a significant number of INH(r)  Mtb clinical isolates without known INH resistance mutations. A laboratory strain, H37Rv, constructed with mabA(g609a) , was resistant to INH. We show here that the mabA(g609a) mutation resulted in the upregulation of inhA, a gene encoding a target for INH, converting the region adjacent to the mutation into an alternative promoter for inhA. The mabA(g609a) silent mutation results in a novel mechanism of INH resistance, filling in a missing piece of INH resistance in Mtb.
authors.affiliation: Department of Infectious Diseases, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku, Tokyo, 162-8655, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ando
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyoshi-Akiyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Watanabe
authors.forename: Teruo
authors.initials: T
authors.lastname: Kirikae
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics*; D024881:Drug Resistance, Bacterial; D015870:Gene Expression; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D010088:Oxidoreductases / Q000096:biosynthesis; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D014376:Tuberculosis / Q000382:microbiology; D015854:Up-Regulation
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid