Whole-genome sequencing has created a revolution in tuberculosis management by providing a comprehensive picture of the various genetic polymorphisms with unprecedented accuracy. Studies mapping genomic heterogeneity in clinical isolates of Mycobacterium tuberculosis using a whole-genome sequencing approach from high tuberculosis burden countries are underrepresented. We report whole-genome sequencing results of 242 clinical isolates of culture-confirmed M. tuberculosis isolates from tuberculosis patients referred to a tertiary care hospital in Southern India. Phylogenetic analysis revealed that the isolates in our study belonged to five different lineages, with Indo-Oceanic (lineage 1, n = 122) and East-African Indian (lineage 3, n = 80) being the most prevalent. We report several mutations in genes conferring resistance to first and second line antitubercular drugs including the genes rpoB, katG, ahpC, inhA, fabG1, embB, pncA, rpsL, rrs, and gyrA. The majority of these mutations were identified in relatively high proportions in lineage 1. Our study highlights the utility of whole-genome sequencing as a potential supplemental tool to the existing genotypic and phenotypic methods, in providing expedited comprehensive surveillance of mutations that may be associated with antitubercular drug resistance as well as lineage characterization of M. tuberculosis isolates. Further larger-scale whole-genome datasets with linked minimum inhibition concentration testing are imperative for resolving the discrepancies between whole-genome sequencing and phenotypic drug sensitivity testing results and quantifying the level of the resistance associated with the mutations for optimization of antitubercular drug and precise dose selection in clinics. IMPORTANCE Studies mapping genetic heterogeneity of clinical isolates of M. tuberculosis for determining their strain lineage and drug resistance by whole-genome sequencing are limited in high tuberculosis burden settings. We carried out whole-genome sequencing of 242 M. tuberculosis isolates from drug-sensitive and drug-resistant tuberculosis patients, identified and collected as part of the TB Portals Program, to have a comprehensive insight into the genetic diversity of M. tuberculosis in Southern India. We report several genetic variations in M. tuberculosis that may confer resistance to antitubercular drugs. Further wide-scale efforts are required to fully characterize M. tuberculosis genetic diversity at a population level in high tuberculosis burden settings for providing precise tuberculosis treatment.
Keywords: Mycobacterium tuberculosis; antitubercular drug resistance; lineage; tuberculosis; whole genome sequencing.