A silent mutation in mabA confers isoniazid resistance on Mycobacterium tuberculosis

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.