Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis

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 and Amit Singh ()
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Vikas Yadav: Indian Institute of Science
Sarthak Sahoo: Indian Institute of Science
Nitish Malhotra: Tata Institute of Fundamental Research (TIFR)
Richa Mishra: École Polytechnique Fédérale de Lausanne
Sreesa Sreedharan: iBRIC Institute for Stem Cell Science and Regenerative Medicine (inStem)
Raju S. Rajmani: Indian Institute of Science
Siva Shanmugam: Foundation for Neglected Disease Research
Radha K. Shandil: Foundation for Neglected Disease Research
Shridhar Narayanan: Foundation for Neglected Disease Research
Vivek V. Thacker: École Polytechnique Fédérale de Lausanne
Sunil Laxman: iBRIC Institute for Stem Cell Science and Regenerative Medicine (inStem)
Mohit Kumar Jolly: Indian Institute of Science
Aswin Sai Narain Seshasayee: Tata Institute of Fundamental Research (TIFR)
Amit Singh: Indian Institute of Science

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64407-w

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