Molecular basis for isoniazid (INH) resistance, one of the front lines drugs used to treat Mycobacterium tuberculosis, is complex. With multidrug-resistant (MDR) tuberculosis (TB) cases increasing annually worldwide, it is imperative to fully understand the molecular basis for INH resistance. The availability of rapid and reliable methods is currently lacking for the detection of INH drug resistance, especially for geographically distinct regions where greater numbers of polymorphisms are observed. Here, we consider TB isolates collected from four high TB burden countries: India, Moldova, Philippines, and South Africa. All isolates were sequenced on Pacific Biosciences for whole genome sequencing (WGS). The analysis yielded three well-documented mutations that alone or in combination account for 91% of INH resistance: katG 315AGC-ACC, inhA promoter -15C-T and -17G-T. 22 novel katG SNPs were found within the INHR isolates and are thought to play a previously undocumented role in INH resistance. We believe the results of this research will provide the greater knowledge of understanding to the complex mechanism of INH resistance in isolates that lack trademark INH-associated mutations.
