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<p>Effective clearance of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular <i>Mtb</i>. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant <i>Mtb</i>, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on <i>Mtb</i> and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced <i>Mtb</i> drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome <i>Mtb</i> drug tolerance.</p>

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Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月23日

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  • Vikas Yadav,
  • Sarthak Sahoo,
  • Nitish Malhotra,
  • Richa Mishra,
  • Sreesa Sreedharan,
  • Raju S. Rajmani,
  • Siva Shanmugam,
  • Radha K. Shandil,
  • Shridhar Narayanan,
  • Vivek V. Thacker,
  • Sunil Laxman,
  • Mohit Kumar Jolly,
  • Aswin Sai Narain Seshasayee,
  • Amit Singh

摘要

Effective clearance of Mycobacterium tuberculosis (Mtb) requires targeting drug-tolerant populations within host macrophages. Here, we show that macrophage metabolic states govern redox heterogeneity and drug response in intracellular Mtb. Using a redox-sensitive fluorescent reporter (Mrx1-roGFP2), flow cytometry, and transcriptomics, we found that macrophages with high oxidative phosphorylation (OXPHOS) and low glycolysis harbor reductive, drug-tolerant Mtb, whereas glycolytically active macrophages generate mitochondrial ROS via reverse electron transport, imposing oxidative stress on Mtb and enhancing drug efficacy. Computational and genetic analyses identified NRF2 as a key regulator linking host metabolism to bacterial redox state and drug tolerance. Pharmacological reprogramming of macrophages with the FDA-approved drug meclizine (MEC) shifted metabolism towards glycolysis, suppressed redox heterogeneity, and reduced Mtb drug tolerance in macrophages and mice. MEC exhibited no adverse interactions with frontline anti-TB drugs. These findings demonstrate the therapeutic potential of host metabolic reprogramming to overcome Mtb drug tolerance.