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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1515627

Phenotypic and genotypic characterization of Mycobacterium tuberculosis pyrazinamide resistance -India, 2018-2020

Provisionally accepted
Sembulingam Tamilzhalagan Sembulingam Tamilzhalagan 1Evanslin S Justin Evanslin S Justin 1Ashok Selvaraj Ashok Selvaraj 1Karthick Venkateswaran Karthick Venkateswaran 1Arun Kumar Sivakumar Arun Kumar Sivakumar 1Heather P Mclaughlin Heather P Mclaughlin 2Patrick K Moonan Patrick K Moonan 2Jonathan P. Smith Jonathan P. Smith 2Sakthi Suba Sakthi Suba 1Mukesh Kumar Sathya Narayanan Mukesh Kumar Sathya Narayanan 1Christine Ho Christine Ho 2Nishant Kumar Nishant Kumar 3Srikanth Prasad Tripathy Srikanth Prasad Tripathy 1Sivakumar Shanmugam Sivakumar Shanmugam 1Patricia J Hall-Eidson Patricia J Hall-Eidson 2Uma Devi Ranganathan Uma Devi Ranganathan 1*
  • 1 National Institute of Research in Tuberculosis (ICMR), Chennai, India
  • 2 Division of Global HIV & TB, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, United States
  • 3 Central Tuberculosis Division, Ministry of Health and Family Welfare (India), Delhi, India

The final, formatted version of the article will be published soon.

    Pyrazinamide (PZA) is a key first-line antituberculosis drug that plays an important role in eradicating persister Mycobacterium tuberculosis (TB) bacilli and shortening the duration of tuberculosis treatment. However, PZA-resistance is on the rise, particularly among persons with multidrug-resistant (MDR) tuberculosis. This nationwide study was conducted to explore the prevalence of mutations conferring PZA resistance, catalogue mutation diversity, investigate the associations of PZA resistance with specific lineages, examine co-resistance to 13 first-and second-line drugs, and evaluate the diagnostic accuracy of sequencing pncA and panD genes for predicting PZA resistance. Whole genome sequencing was performed on 2,207 M. tuberculosis isolates from 25 States and 4 Union Territories of India. The majority of phenotypically PZA-resistant isolates (77%) harbored 171 distinct mutations in pncA; however, a small number of mutations in panD, rpsA and ClpC1 were also observed. A set of novel mutations associated PZA resistance was uncovered, along with an additional 143 PZA resistance-conferring mutations in pncA based on application of WHO-endorsed grading rules. PZA resistance was predominately observed in Lineage 2 and eight lineage-specific resistance markers were identified. Mutations distributed across pncA correlate to 94% of PZA resistance and were the predominant drivers of phenotypic resistance; evidence generated herein substantiates sequencing the entire gene and promoter for comprehensive genotypic-based prediction of PZA resistance. This work provides key insights into the scope of PZA-resistance in India, a high drug-resistant TB burden country, and can support the effectiveness of TB prevention and control efforts.* Polydrug-resistant tuberculosis = resistance to two or more antituberculosis drugs and not classified MDR, pre-XDR or XDR. ** Total percent agreement between gDST and pDST for pyrazinamide was determined used genotypic resistance determination as a denominator because sequencing is the most likely gold standard for resistance determination of this antituberculosis drug.

    Keywords: Tuberculosis, Drug Resistance, Drug susceptibility testing, Genetic mutations, whole genome sequencing, Pyrazinamide, PZA

    Received: 23 Oct 2024; Accepted: 29 Nov 2024.

    Copyright: © 2024 Tamilzhalagan, Justin, Selvaraj, Venkateswaran, Sivakumar, Mclaughlin, Moonan, Smith, Suba, Sathya Narayanan, Ho, Kumar, Tripathy, Shanmugam, Hall-Eidson and Ranganathan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Uma Devi Ranganathan, National Institute of Research in Tuberculosis (ICMR), Chennai, India

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.