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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),...

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Main Authors: Yadav, Vikas (Author) , Sahoo, Sarthak (Author) , Malhotra, Nitish (Author) , Mishra, Richa (Author) , Sreedharan, Sreesa (Author) , Rajmani, Raju S. (Author) , Shanmugam, Siva (Author) , Shandil, Radha K. (Author) , Narayanan, Shridhar (Author) , Thacker, Vivek Vijay (Author) , Laxman, Sunil (Author) , Jolly, Mohit Kumar (Author) , Seshasayee, Aswin Sai Narain (Author) , Singh, Amit (Author)
Format: Article (Journal)
Language:English
Published: 23 October 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-20
ISSN:2041-1723
DOI:10.1038/s41467-025-64407-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-64407-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-64407-w
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Author Notes: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
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Summary: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.
Item Description:Online veröffentlicht: 23. Oktober 2025
Gesehen am 08.12.2025
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-64407-w

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