
@article {161133,
	title = {Bioenergetic reprogramming of macrophages reduces drug tolerance in Mycobacterium tuberculosis.},
	journal = {Nat Commun},
	volume = {16},
	year = {2025},
	month = {2025 Oct 23},
	pages = {9370},
	abstract = {<p>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.</p>
},
	keywords = {Animals, Antitubercular Agents, Drug Tolerance, Energy Metabolism, Female, Glycolysis, Humans, Macrophages, Mice, Mice, Inbred C57BL, Mitochondria, Mycobacterium tuberculosis, NF-E2-Related Factor 2, Oxidation-Reduction, Oxidative Phosphorylation, Oxidative Stress, Reactive Oxygen Species, Tuberculosis},
	issn = {2041-1723},
	doi = {10.1038/s41467-025-64407-w},
	author = {Yadav, Vikas and Sahoo, Sarthak and Malhotra, Nitish and Mishra, Richa and Sreedharan, Sreesa and Rajmani, Raju S and Shanmugam, Siva and Shandil, Radha K and Narayanan, Shridhar and Thacker, Vivek V and Laxman, Sunil and Jolly, Mohit Kumar and Seshasayee, Aswin Sai Narain and Singh, Amit}
}
@article {137347,
	title = {Cysteine desulfurase (IscS)-mediated fine-tuning of bioenergetics and SUF expression prevents  hypervirulence.},
	journal = {Sci Adv},
	volume = {9},
	year = {2023},
	month = {2023 Dec 15},
	pages = {eadh2858},
	abstract = {<p>Iron-sulfur (Fe-S) biogenesis requires multiprotein assembly systems, SUF and ISC, in most prokaryotes. () encodes a complete SUF system, the depletion of which was bactericidal. The ISC operon is truncated to a single gene (cysteine desulfurase), whose function remains uncertain. Here, we show that Δ is bioenergetically deficient and hypersensitive to oxidative stress, antibiotics, and hypoxia. Δ resisted killing by nitric oxide (NO). RNA sequencing indicates that IscS is important for expressing regulons of DosR and Fe-S-containing transcription factors, WhiB3 and SufR. Unlike wild-type , Δ could not enter a stable persistent state, continued replicating in mice, and showed hypervirulence. The operon was overexpressed in Δ during infection in a NO-dependent manner. Suppressing expression in Δ either by CRISPR interference or upon infection in inducible NO-deficient mice arrests hypervirulence. Together, redesigned the ISC system to "fine-tune" the expression of SUF machinery for establishing persistence without causing detrimental disease in the host.</p>
},
	keywords = {Animals, Energy Metabolism, Escherichia coli, Iron-Sulfur Proteins, Mice, Mycobacterium tuberculosis},
	issn = {2375-2548},
	doi = {10.1126/sciadv.adh2858},
	author = {Das, Mayashree and Sreedharan, Sreesa and Shee, Somnath and Malhotra, Nitish and Nandy, Meghna and Banerjee, Ushashi and Kohli, Sakshi and Rajmani, Raju S and Chandra, Nagasuma and Seshasayee, Aswin Sai Narain and Laxman, Sunil and Singh, Amit}
}
