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<p>The rapid emergence of multidrug-resistant <i>Mycobacterium tuberculosis</i> (Mtb) threatens global tuberculosis (TB) control, yet the mechanisms enabling rapid evolution of resistance in Mtb remain poorly understood. Here, we show that pre-existing mutations in oxidative stress response genes create permissive genomic backgrounds that accelerate high-level isoniazid resistance (INH<sup>R</sup>), challenging the paradigm that resistance mutations must precede compensatory adaptation. Using <i>Mycobacterium smegmatis</i> mc<sup>2</sup>155 (Msm) as a model, we demonstrate that brief exposure to sublethal isoniazid (INH) enriches for “low-level resistance and tolerance” (LLRT) mutants in a single step. LLRT mutants, particularly those with <i>ohrR</i> loss-of-function mutations, acquire high-level resistance (&gt;500× IC<sub>50</sub>) at ~6-fold higher rates than wildtype, primarily through otherwise deleterious mycothiol biosynthesis mutations that become tolerable in an oxidative stress-buffered background. Crucially, sublethal oxidative stress alone, mimicking host immune pressure, nearly tripled the rate of INH<sup>R</sup> evolution. Analysis of 1578 clinical Mtb isolates revealed significant enrichment of oxidative stress-related loci among those associated with INH<sup>R</sup>. Reanalysis of genome-wide CRISPRi data further linked oxidative stress response pathways to survival under multiple antibiotics. Together, these findings suggest that host-imposed oxidative stress and suboptimal drug exposure may prime Mtb populations for rapid resistance evolution, highlighting oxidative stress defenses as potential targets to limit resistance emergence.</p>

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Host oxidative stress primes mycobacteria for rapid antibiotic resistance evolution

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月7日

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  • Evan Pepper-Tunick,
  • Vivek Srinivas,
  • Fred D. Mast,
  • Song Li,
  • Sagan Russ,
  • Weston Hanson,
  • Amy D. Zamora,
  • Wei-Ju Wu,
  • Matthew Silcocks,
  • Dang Thi Minh Ha,
  • Sarah J. Dunstan,
  • Thuong Nguyen Thuy Thuong,
  • Serdar Turkarslan,
  • John D. Aitchison,
  • Mario L. Arrieta-Ortiz,
  • Nitin S. Baliga

摘要

The rapid emergence of multidrug-resistant Mycobacterium tuberculosis (Mtb) threatens global tuberculosis (TB) control, yet the mechanisms enabling rapid evolution of resistance in Mtb remain poorly understood. Here, we show that pre-existing mutations in oxidative stress response genes create permissive genomic backgrounds that accelerate high-level isoniazid resistance (INHR), challenging the paradigm that resistance mutations must precede compensatory adaptation. Using Mycobacterium smegmatis mc2155 (Msm) as a model, we demonstrate that brief exposure to sublethal isoniazid (INH) enriches for “low-level resistance and tolerance” (LLRT) mutants in a single step. LLRT mutants, particularly those with ohrR loss-of-function mutations, acquire high-level resistance (>500× IC50) at ~6-fold higher rates than wildtype, primarily through otherwise deleterious mycothiol biosynthesis mutations that become tolerable in an oxidative stress-buffered background. Crucially, sublethal oxidative stress alone, mimicking host immune pressure, nearly tripled the rate of INHR evolution. Analysis of 1578 clinical Mtb isolates revealed significant enrichment of oxidative stress-related loci among those associated with INHR. Reanalysis of genome-wide CRISPRi data further linked oxidative stress response pathways to survival under multiple antibiotics. Together, these findings suggest that host-imposed oxidative stress and suboptimal drug exposure may prime Mtb populations for rapid resistance evolution, highlighting oxidative stress defenses as potential targets to limit resistance emergence.