Mycobacterium tuberculosis Lineages Associated with Mutations and Drug Resistance in Isolates from India

Siva Kumar Shanmugam, Narender Kumar, Tamilzhalagan Sembulingam, Suresh Babu Ramalingam, Ashok Selvaraj, Udhayakumar Rajendhiran, Sudha Solaiyappan, Srikanth P. Tripathy, Mohan Natrajan, Padmapriyadarsini Chandrasekaran, Soumya Swaminathan, Julian Parkhill, Sharon J. Peacock, Uma Devi K. Ranganathan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Current knowledge on resistance-conferring determinants in Mycobacterium tuberculosis is biased toward globally dominant lineages 2 and 4. In contrast, lineages 1 and 3 are predominant in India. In this study, we performed whole-genome sequencing of 498 MDR M. tuberculosis isolates from India to determine the prevalence of drug resistance mutations and to understand the genomic diversity. A retrospective collection of 498 M. tuberculosis isolates submitted to the National Institute for Research in Tuberculosis for phenotypic susceptibility testing between 2014 to 2016 were sequenced. Genotypic resistance prediction was performed using known resistance-conferring determinants. Genotypic and phenotypic results for 12 antituberculosis drugs were compared, and sequence data were explored to characterize lineages and their association with drug resistance. Four lineages were identified although lineage 1 predominated (43%). The sensitivity of prediction for isoniazid and rifampicin was 92% and 98%, respectively. We observed lineage-specific variations in the proportion of isolates with resistance-conferring mutations, with drug resistance more common in lineages 2 and 3. Disputed mutations (codons 430, 435, 445, and 452) in the rpoB gene were more common in isolates other than lineage 2. Phylogenetic analysis and pairwise SNP difference revealed high genetic relatedness of lineage 2 isolates. WGS based resistance prediction has huge potential, but knowledge of regional and national diversity is essential to achieve high accuracy for resistance prediction. IMPORTANCE Current knowledge on resistance-conferring determinants in Mycobacterium tuberculosis is biased toward globally dominant lineages 2 and 4. In contrast, lineages 1 and 3 are predominant in India. We performed whole-genome sequencing of 498 MDR M. tuberculosis isolates from India to determine the prevalence of drug resistance mutations and to understand genomic diversity. Four lineages were identified although lineage 1 predominated (43%). The sensitivity of prediction for isoniazid and rifampicin was 92% and 98%, respectively. We observed lineage-specific variations in the proportion of isolates with resistance-conferring mutations, with drug resistance more common in lineages 2 and 3. Disputed mutations (codons 430, 435, 445, and 452) in the rpoB gene were more common in isolates other than lineage 2. Phylogenetic analysis and pairwise SNP difference revealed high genetic relatedness of lineage 2 isolates. WGS based resistance prediction has huge potential, but knowledge of regional and national diversity is essential to achieve high accuracy for resistance prediction.

Original languageEnglish
JournalMicrobiology Spectrum
Volume10
Issue number3
DOIs
Publication statusPublished - Jun 2022
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the UK Medical Research Council (X5 06489 DBT-MRC Joint Centre Partnership) and the Department of Biotechnology, India (BT/IN/DBT-MRC [UK]/12/SS/2015-2016 for ICMR-National Institute for Research in Tuberculosis) as a Cambridge Chennai Partnership on Antimicrobial Resistant Tuberculosis. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The WGS data derived from this study was not used for patient management. We declare no conflict of interest.

Publisher Copyright:
Copyright © 2022 Shanmugam et al.

Keywords

  • Mycobacterium tuberculosis
  • drug resistance
  • lineage
  • whole-genome sequencing

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