Tamilzhalagan Sembulingam, Justin Evanslin Santus, Selvaraj Ashok, Venkateswaran Karthick, Sivakumar Arun Kumar, Chittibabu Suganthi, McLaughlin Heather P, Moonan Patrick K, Smith Jonathan P, Suba Sakthi, Sathya Narayanan Mukesh Kumar, Ho Christine S, Kumar Nishant, Tripathy Srikanth P, Shanmugam Siva K, Hall-Eidson Patricia J, Ranganathan Uma Devi
National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chennai, India.
Division of Global HIV and Tuberculosis, U.S. Centers for Disease Control and Prevention, Atlanta, GA, United States.
Front Microbiol. 2025 Jan 8;15:1515627. doi: 10.3389/fmicb.2024.1515627. eCollection 2024.
Pyrazinamide (PZA) is a key first-line antituberculosis drug that plays an important role in eradicating persister (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 A and D genes for predicting PZA resistance. Whole genome sequencing was performed on 2,207 isolates from 25 States and 4 Union Territories of India. The majority of phenotypically PZA-resistant isolates (77%) harbored 171 distinct mutations in A; however, a small number of mutations in D, A and C1 were also observed. A set of novel mutations associated PZA resistance was uncovered, along with an additional 143 PZA resistance-conferring mutations in A 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 A 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.
吡嗪酰胺（PZA）是一种关键的一线抗结核药物，在根除持留菌（结核）杆菌和缩短结核病治疗疗程方面发挥着重要作用。然而，对PZA的耐药性正在上升，尤其是在耐多药（MDR）结核病患者中。开展这项全国性研究旨在探索赋予PZA耐药性的突变流行情况、梳理突变多样性、调查PZA耐药性与特定谱系的关联、检测对13种一线和二线药物的共耐药性，并评估测序A和D基因预测PZA耐药性的诊断准确性。对来自印度25个邦和4个中央直辖区的2207株分离株进行了全基因组测序。大多数表型耐PZA的分离株（77%）在A基因中存在171种不同的突变；不过，在D、A和C1基因中也观察到少量突变。发现了一组与PZA耐药性相关的新突变，根据世界卫生组织认可的分级规则，在A基因中还发现了另外143种赋予PZA耐药性的突变。PZA耐药性主要在谱系2中观察到，并鉴定出8个谱系特异性耐药标志物。分布在A基因上的突变与94%的PZA耐药性相关，是表型耐药性的主要驱动因素；本文产生的证据证实对整个基因和启动子进行测序可用于基于基因型全面预测PZA耐药性。这项工作为印度这个结核病耐药负担高的国家的PZA耐药范围提供了关键见解，并可支持结核病防控工作的有效性。
