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<p>The emergence of drug-resistant <i>Mycobacterium tuberculosis</i> strains presents a significant challenge to tuberculosis (TB) control programmes worldwide, particularly in high-burden countries, such as Pakistan. This study characterises the genomic diversity and drug resistance mutation profiles of <i>M. tuberculosis</i> isolates from Khyber Pakhtunkhwa using whole-genome sequencing (WGS). A total of 35 clinical <i>M. tuberculosis</i> isolates underwent WGS. Sequence data were quality-filtered and mapped to the H37Rv reference genome, characterising variants, including single-nucleotide polymorphisms (SNPs). Lineage classification, drug resistance profiling, and identification of resistance mutations were performed using TB-Profiler software. SNP-based clustering was used to infer recent transmission events. All four major&#xa0;<i>M. tuberculosis</i>&#xa0;lineages (L1–L4) were detected; however, more than half of the isolates belonged to lineage L3 (CAS, <i>n</i> = 19; 54.3%). Almost all isolates were drug-resistant (34/35), including pre-extensively drug-resistant (pre-XDR,&#xa0;<i>n</i> = 15; 42.9%) and multidrug-resistant (MDR,&#xa0;<i>n</i> = 14; 40.0%) strains. The most frequent resistance-associated mutations included&#xa0;<i>katG</i> S315T&#xa0;(27/35) and&#xa0;<i>inhA</i> c.-777C &gt; T&#xa0;(4/35) for isoniazid resistance,&#xa0;<i>rpoB</i> S450L&#xa0;(24/35) for rifampicin resistance,&#xa0;<i>embB</i> M306I/V (18/35) for ethambutol resistance, and&#xa0;<i>gyrA</i> D94G&#xa0;(8/35) and A90V&#xa0;(5/35) for fluoroquinolone resistance. Compensatory mutations were observed in&#xa0;<i>rpoC</i> and&#xa0;<i>ahpC</i>. Mutations associated with bedaquiline and clofazimine resistance (<i>mmpR5</i> c.140dupA,&#xa0;c.138_139dupTG) were detected in single isolates. Interestingly, one isolate exhibited a deletion encompassing&#xa0;<i>mmpR5, mmpL5</i>, and <i>mmpS5</i>, potentially increasing bedaquiline susceptibility. Phylogenetic analysis using 6,635 genome-wide SNPs identified two transmission clusters with &lt; 9 SNPs differences, suggesting ongoing local transmission. These results highlight the presence of drug-resistant&#xa0;<i>M. tuberculosis</i>&#xa0;strains in Khyber Pakhtunkhwa, encompassing both globally recognised and novel resistance-associated mutations. Our findings underscore the critical need to integrate WGS into TB surveillance and control programmes in Pakistan to guide targeted interventions and curb the spread of resistant strains.</p>

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Whole-genome analysis of drug resistance and transmission patterns in Mycobacterium tuberculosis from Khyber Pakhtunkhwa, Pakistan

  • 期刊论文

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  • 发表日期：

    2026年7月22日

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  • Muhammad Fayaz Khan,
  • Jody Phelan,
  • Anwar Sheed Anwar,
  • Sadiq Noor Khan,
  • Amjad Ali,
  • Faryal Mehwish Awan,
  • Ayesha Obaid,
  • Dawood Ahmad,
  • Afshan Saleem,
  • Susana Campino,
  • Taane G. Clark,
  • Abdul Jabbar

摘要

The emergence of drug-resistant Mycobacterium tuberculosis strains presents a significant challenge to tuberculosis (TB) control programmes worldwide, particularly in high-burden countries, such as Pakistan. This study characterises the genomic diversity and drug resistance mutation profiles of M. tuberculosis isolates from Khyber Pakhtunkhwa using whole-genome sequencing (WGS). A total of 35 clinical M. tuberculosis isolates underwent WGS. Sequence data were quality-filtered and mapped to the H37Rv reference genome, characterising variants, including single-nucleotide polymorphisms (SNPs). Lineage classification, drug resistance profiling, and identification of resistance mutations were performed using TB-Profiler software. SNP-based clustering was used to infer recent transmission events. All four major M. tuberculosis lineages (L1–L4) were detected; however, more than half of the isolates belonged to lineage L3 (CAS, n = 19; 54.3%). Almost all isolates were drug-resistant (34/35), including pre-extensively drug-resistant (pre-XDR, n = 15; 42.9%) and multidrug-resistant (MDR, n = 14; 40.0%) strains. The most frequent resistance-associated mutations included katG S315T (27/35) and inhA c.-777C > T (4/35) for isoniazid resistance, rpoB S450L (24/35) for rifampicin resistance, embB M306I/V (18/35) for ethambutol resistance, and gyrA D94G (8/35) and A90V (5/35) for fluoroquinolone resistance. Compensatory mutations were observed in rpoC and ahpC. Mutations associated with bedaquiline and clofazimine resistance (mmpR5 c.140dupA, c.138_139dupTG) were detected in single isolates. Interestingly, one isolate exhibited a deletion encompassing mmpR5, mmpL5, and mmpS5, potentially increasing bedaquiline susceptibility. Phylogenetic analysis using 6,635 genome-wide SNPs identified two transmission clusters with < 9 SNPs differences, suggesting ongoing local transmission. These results highlight the presence of drug-resistant M. tuberculosis strains in Khyber Pakhtunkhwa, encompassing both globally recognised and novel resistance-associated mutations. Our findings underscore the critical need to integrate WGS into TB surveillance and control programmes in Pakistan to guide targeted interventions and curb the spread of resistant strains.