Reprogramming immune cells to make TB drugs work better

Tuberculosis remains a global health problem because Mycobacterium tuberculosis (Mtb) can survive inside the body’s immune cells, making eradication difficult. One reason is that Mtb does not behave uniformly inside macrophages; individual bacteria show differences in redox metabolism that help them survive anti-TB drugs. Until now it has been unclear whether features of the host cell itself — the macrophage — are linked to this bacterial redox diversity and to drug tolerance. In work led by corresponding author Amit Singh, researchers set out to connect the physiology of infected macrophages with the redox state and drug sensitivity of the Mtb populations they contain. Rather than studying bacteria in isolation, the team examined live infected macrophages to see how variations in the host cell’s energy use and gene activity relate to whether the bacteria inside are in a drug-tolerant state. Their goal was to find host-directed strategies that could make existing anti-TB drugs more effective by altering the environment inside macrophages where Mtb hides.

To probe this host–pathogen relationship the authors used a fluorescent reporter of mycobacterial redox potential together with flow sorting and RNA sequencing of infected macrophages to separate and profile cells that harbored different Mtb redox states. They found a striking association between macrophage bioenergetics and bacterial redox: macrophages with suppressed glycolysis and elevated oxidative phosphorylation (OXPHOS) correlated with Mtb populations exhibiting reductive stress and drug tolerance. By contrast, macrophages with elevated glycolysis and suppressed OXPHOS showed higher mitochondrial reactive oxygen species through reverse electron transport, which produced oxidative stress in Mtb and enhanced drug efficacy. Computational and genetic approaches identified Nrf2 as a key regulator of macrophage bioenergetics driving redox heterogeneity and drug tolerance in Mtb. The team redirected macrophage metabolism from OXPHOS to glycolysis using the FDA-approved antiemetic drug meclizine and observed that this intervention subverted redox heterogeneity and diminished drug tolerance in macrophages and mice. The pharmacological profile of meclizine (C max and AUC last) indicated no adverse interactions with first-line anti-TB drugs in mice.

These findings demonstrate the feasibility of a host-directed approach that reprograms macrophage metabolism to reduce bacterial drug tolerance during Mtb infection. By linking specific metabolic states in macrophages to protective or permissive environments for bacteria, the study highlights targets such as Nrf2 and metabolic pathways like glycolysis and oxidative phosphorylation (OXPHOS) as levers to sensitize intracellular Mtb to treatment. The successful use of meclizine, an already FDA-approved drug, points to a possible shortcut for translation because of existing safety and pharmacology data; in mice it both reduced drug tolerance and showed no detected adverse interaction with first-line anti-TB drugs. While these results come from experiments in macrophages and mouse models, they provide proof of principle that repurposing host-targeted drugs could complement conventional antibiotics, potentially improving outcomes against hard-to-kill bacterial populations and guiding further preclinical and clinical work.