Could rewiring macrophage metabolism make TB treatments shorter?

Thebacteria that cause tuberculosis (TB) also infect macrophages, the very immune cells meant to capture and destroy them. Once inside, the bacteria create a niche where they can persist for months or even years, tolerating even powerful antibiotics. This resilience is a major reason TB treatment requires long, intensive drug regimens lasting six to nine months, leading to poor patient adherence, extended antibiotic exposure, and often drug resistance.

In a new study in Nature Communications, researchers from around India have suggested that the key to outsmarting the bacteria, Mycobacterium tuberculosis (Mtb), may not lie in new antibiotics but in rewiring the metabolism of host macrophages, potentially paving the way for shorter and more effective anti-TB therapies.

Oxidative stress

Macrophages use several strategies to kill microbes, including bursts of oxidative stress in the form of unstable molecules that can damage cellular components. Amit Singh of the Centre for Infectious Disease Research at the Indian Institute of Science, Bengaluru, and the study’s corresponding author said they previously observed striking metabolic differences among Mtb cells growing inside macrophages. Specifically, bacteria with a greater ability to counter oxidative stress were markedly more drug-tolerant than those with weaker defences.

“We observed this phenomenon only when bacteria invaded macrophages, which led us to suspect that macrophage-specific mechanisms were shaping the metabolic states of Mtb,” Dr. Singh said.

The researchers infected mouse macrophages with Mtb engineered to carry a fluorescent sensor: its readout rose when the bacteria were more oxidised and fell when they were more reduced. When they compared the gene activity patterns of macrophages carrying the two Mtb populations, they noted a pattern. Macrophages with reduced Mtb relied on oxidative phosphorylation (OXPHOS), a process by which mitochondria generate energy using oxygen. On the other hand, macrophages with oxidised Mtb had higher glycolysis, an alternate pathway that generates energy by breaking down glucose.

These distinct metabolic states influenced how well Mtb tolerated antibiotics against both drug-sensitive and drug-resistant TB, the researchers said.

In Dr. Singh’s words: “Glycolytically-driven macrophages harbour impaired mitochondria and experience higher oxidative stress, making the bacteria more oxidised and susceptible to anti-TB drugs. Conversely, bacteria within OXPHOS-driven macrophages … can better neutralise oxidative stress, allowing them to tolerate drugs more effectively.”

Vikas Yadav, a former PhD scholar in Singh’s lab and the study’s first author, added, “Uninfected macrophages were metabolically reprogrammed by signals from infected cells, suggesting that infection reshapes the whole microenvironment, not just infected cells.”

A key player

The team also identified a regulatory molecule that linked macrophage metabolism to bacterial survival. Macrophages harbouring reduced, drug-tolerant Mtb expressed high levels of NRF2, a protein that boosted antioxidant responses. When the researchers inhibited NRF2, oxidative stress increased and macrophages shifted towards glycolysis. This metabolic switch made previously tolerant bacteria far more susceptible to isoniazid, a frontline anti-TB drug.

“We were surprised to find that NRF2, normally protective for host cells, actually supported a drug-tolerant niche for Mtb, by maintaining high OXPHOS and low oxidative stress conditions,” Dr. Yadav said.

According to Raghunand R. Tirumalai, senior principal scientist at the CSIR-Centre for Cellular and Molecular Biology, Hyderabad, who wasn’t involved in the study, the findings raise the possibility that Mtb may actively manipulate NRF2 levels to ensure it survives antibiotic treatment. Identifying the bacterial factors involved, he added, could be an important direction for future investigations.

Old drug, new role

When researchers suppressed OXPHOS, oxidative stress increased, macrophages shifted towards glycolysis, and Mtb became more sensitive to antibiotics. On the other hand, conditions that favoured OXPHOS supported a reduced state and allowed Mtb to tolerate drugs better, showing how host cell metabolism directly affected drug response.

The researchers also looked for existing drugs that could steer Mtb-infected macrophages towards glycolysis. This led them to meclizine, an over-the-counter drug widely used to treat nausea and motion sickness. Meclizine has long been known to redirect mammalian cells from OXPHOS to glycolysis and has a good safety record. In infected macrophages, the team reported, meclizine spiked oxidative stress and glycolytic activity. It also dramatically lowered Mtb’s tolerance to frontline anti-TB drugs, with no signs of harmful drug-drug interactions.

In a mouse model that mirrored human TB, combined treatment with isoniazid and meclizine produced an additional 20x decrease in the bacterial load.

“This observation opens up avenues to identify additional host-targeting compounds that have the potential for switching macrophage metabolism to a drug susceptible state, and can synergise with conventional anti-TB drugs that target the bacterium,” Dr. Tirumalai said.

The lungs of meclizine-treated animals showed signs of tissue recovery, underscoring its broader therapeutic potential. Dr. Singh emphasised that this finding is significant because at least half of TB survivors still suffer lasting lung damage and impaired lung function.

“In addition to improving treatment efficacy, a drug combination including meclizine can activate the immune system, promote healing of the TB cavity, and restore lung function,” Dr. Singh said.

Next challenge

Host-directed therapies like meclizine boost host defences without directly attacking bacteria, bypassing the risk of antibiotic resistance. Nisheeth Agarwal of the Translational Health Science and Technology Institute in Faridabad and also an independent researcher said, “Given the rising incidence of antimicrobial resistance in Mtb, such therapies provide a relatively promising approach as adjunctive anti-TB therapies by potentiating their effects or enhancing drug availability.”

The next challenge, according to the researchers, is to understand how meclizine can be safely paired with existing treatments to maximise bacterial clearance and prevent relapse, without adding side effects. Because meclizine crosses the blood–brain barrier, it may also enhance the effectiveness of anti-TB drugs that struggle to reach therapeutic levels in the central nervous system.

If clinical studies in humans confirm meclizine can shorten treatment duration, Dr. Singh said, it could improve patient adherence, reduce transmission, and help curb the rise of drug resistance.

Shweta Yogi is a freelance science writer.