Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis
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.
Authors
- Shridhar Narayanan (ORCID: https://orcid.org/0000-0002-7781-7399)
- Richa Mishra (ORCID: https://orcid.org/0000-0001-8786-8432)
- Vikas Yadav (ORCID: https://orcid.org/0000-0002-2372-1463)
- Aswin Sai Narain Seshasayee (ORCID: https://orcid.org/0000-0001-7028-1803)
- Siva Kumar Shanmugam
- Vivek V. Thacker (ORCID: https://orcid.org/0000-0002-1681-627X)
- Sarthak Sahoo (ORCID: https://orcid.org/0000-0002-7771-5894)
- Amit Singh (ORCID: https://orcid.org/0000-0001-6761-1664)
- Nitish Malhotra (ORCID: https://orcid.org/0000-0001-8580-9623)
- Radha Krishan Shandil (ORCID: https://orcid.org/0000-0002-0908-1340)
- Sreesa Sreedharan (ORCID: https://orcid.org/0000-0003-2329-477X)
- Mohit Kumar Jolly (ORCID: https://orcid.org/0000-0002-6631-2109)
- Sunil Laxman (ORCID: https://orcid.org/0000-0002-0861-5080)
- Raju S Rajmani
Institutions
- Tata Institute of Fundamental Research (IN)
- National Centre for Biological Sciences (IN)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Foundation for Neglected Disease Research (IN)
- École Polytechnique Fédérale de Lausanne (CH)
- Indian Institute of Science Bangalore (IN)
- SASTRA University (IN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1038/s41467-025-64407-w
- Primary Topic
- Chemical Reactions and Isotopes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Indian Institute of Science
- Department of Science and Technology, Ministry of Science and Technology, India
- Department of Atomic Energy, Government of India
- École Polytechnique Fédérale de Lausanne
- Holcim Stiftung zur Förderung der Wissenschaftlichen Fortbildung
- National Centre for Biological Sciences