GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis

  1. Saba Naz
  2. Kumar Paritosh
  3. Priyadarshini Sanyal
  4. Sidra Khan
  5. Yogendra Singh
  6. Umesh Varshney
  7. Vinay Kumar Nandicoori  Is a corresponding author
  1. Centre for Cellular and Molecular Biology, India
  2. University of Delhi, India
  3. National Institute of Immunology, India
  4. Indian Institute of Science Bangalore, India

Abstract

The emergence of drug resistance in Mycobacterium tuberculosis (Mtb) is alarming and demands in-depth knowledge for timely diagnosis. We performed genome-wide association analysis (GWAS) using 2237 clinical strains of Mtb to identify novel genetic factors that evoke drug resistance. In addition to the known direct targets, we identified for the first time, a strong association between mutations in DNA repair genes and the multidrug-resistant phenotype. To evaluate the impact of variants identified in the clinical samples in the evolution of drug resistance, we utilized knockouts and complemented strains in Mycobacterium smegmatis (Msm) and Mtb. Results show that variant mutations compromised the functions of MutY and UvrB. MutY variant showed enhanced survival compared with wild-type (Rv) when the Mtb strains were subjected to multiple rounds of ex vivo antibiotic stress. In an in vivo guinea pig infection model, the MutY variant outcompeted the wild-type strain. We show that novel variant mutations in the DNA repair genes collectively compromise their functions and contribute to better survival under antibiotic/host stress conditions.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file.Sequencing data have been deposited at NCBI under Bioproject PRJNA885615.Code availability atGitHub: https://github.com/kumar-paritosh/analysis_of_Mtb_genome

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Saba Naz

    Centre for Cellular and Molecular Biology, Hyderabad, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Kumar Paritosh

    Center for Genetic Manipulation of Crop Plants, University of Delhi, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Priyadarshini Sanyal

    National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Sidra Khan

    National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Yogendra Singh

    Department of Zoology, University of Delhi, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3902-4355
  6. Umesh Varshney

    Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3196-5908
  7. Vinay Kumar Nandicoori

    National Institute of Immunology, New Delhi, India
    For correspondence
    vinaykn@nii.ac.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5682-4178

Funding

Department of Biotechnology, Ministry of Science and Technology, India (BT/PR13522/COE/34/27/2015)

  • Vinay Kumar Nandicoori

Department of Science and Technology, Ministry of Science and Technology, India (JCB/2019/000015)

  • Vinay Kumar Nandicoori

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal experiments protocol was approved by the Animal Ethics Committee of the National Institute of Immunology, New Delhi, India. The approval (IAEC#409/16) is as per the guidelines issued by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India.

Reviewing Editor

  1. Digby F Warner, University of Cape Town, South Africa

Version history

  1. Received: November 25, 2021
  2. Preprint posted: January 4, 2022 (view preprint)
  3. Accepted: January 11, 2023
  4. Accepted Manuscript published: January 25, 2023 (version 1)
  5. Version of Record published: January 25, 2023 (version 2)
  6. Version of Record updated: February 2, 2023 (version 3)

Copyright

© 2023, Naz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Saba Naz
  2. Kumar Paritosh
  3. Priyadarshini Sanyal
  4. Sidra Khan
  5. Yogendra Singh
  6. Umesh Varshney
  7. Vinay Kumar Nandicoori
(2023)
GWAS and functional studies suggest a role for altered DNA repair in the evolution of drug resistance in Mycobacterium tuberculosis
eLife 12:e75860.
https://doi.org/10.7554/eLife.75860

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