Anti-nausea drug could be used against drug-resistant TB

A radical strategy to tackle drug-resistant tuberculosis could involve reprogramming the metabolism of immune cells called macrophages. This approach makes the bacteria they harbour more sensitive to existing antibiotics rather than attacking the microbes directly, a new study shows¹.

Meclizine, an FDA-approved anti-nausea drug, could safely alter macrophage metabolism, says Amit Singh at the Indian Institute of Science, Bangalore, who led the study in collaboration with the National Centre for Biological Sciences, iBRIC Institute for Stem Cell Science and Regenerative Medicine, Foundation for Neglected Disease Research, Bangalore, and École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

This approach may shorten the treatment of TB, says biochemist and TB researcher Ramandeep Singh at the Translational Health Science and Technology Institute, Faridabad.

India recorded a third of the globe’s multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB) in 2024, according to the WHO Global TB Report 2025.

Patients infected with such bacteria that outsmart first-line antibiotics (isoniazid, rifampicin, pyrazinamide and ethambutol) are forced to go through prolonged antibiotic-based treatment regimens. TB bacteria live and survive in macrophages — immune cells that usually engulf and kill bacteria. In fact, they prefer macrophages that generate energy via the metabolic pathway oxidative phosphorylation (OXPHOS). Macrophages that use another route, called glycolysis, to generate energy, make life harder for the bacteria.

This preference creates a geographic divide in the lungs. OXPHOS-dependent macrophages in the alveoli of the lungs harbour far more bacteria than glycolysis-dependent macrophages in the interstitium. But “whether these distinct metabolic programmes also influence the bacteria’s ability to tolerate drugs was unclear,” Singh says.

The team used a fluorescent reporter (Mtb-roGFP2) to measure the internal reduction/oxidation state of bacteria. They found bacteria with a reductive state were more drug-tolerant and were primarily in OXPHOS-dependent macrophages. However, bacteria with an oxidized state were more susceptible to drugs and were found in glycolysis-dependent macrophages.  

That’s where meclizine came in. “Meclizine promoted glycolytic metabolism across diverse mammalian cells without inducing toxicity, making it a promising candidate,” Singh notes.

Host-directed therapy gains momentum

Although meclizine has been FDA-approved since the 1950s, its ability to shift cellular metabolism was only discovered in 2010². Singh’s group focused on meclizine because of its long safety record, consistent metabolic effects across cell types, and reliability compared with other modulators like metformin.

In mice with TB, meclizine caused no adverse reactions when combined with first-line antibiotics, suggesting it could safely complement standard treatment. This prompted Singh and colleagues to explore repurposing the drug as part of a more effective regimen against drug-resistant tuberculosis.

“Meclizine makes the existing TB drugs work much better,” says Singh. “It enhances the efficacy of medicines used to treat drug-resistant TB, such as moxifloxacin.”

A combination treatment of meclizine and isoniazid reduced bacterial levels in the lungs 20-fold lower than those treated with isoniazid alone. It reduced lung inflammation, increased glycolysis-driven interstitial macrophages, and decreased OXPHOS-preferring alveolar macrophages.

This idea of host-directed therapy — targeting the host’s own cells and processes to stop the bacteria from thriving — has been gaining steam. Nonetheless, “they are restricted to trials or individualised off-label use,” says Ruchi Jain Dey, at Birla Institute of Technology And Science, Pilani, Hyderabad. In off-label use, FDA-approved drugs for other conditions are used to help patients in their TB treatment.

Another factor that makes meclizine attractive is its ability to cross the blood-brain barrier, making it a promising candidate for treating TB meningitis.

Determining the right dosage of meclizine and confirming its safety in humans will require further study, as translating promising findings from animals to people often fails. Ramakrishnan S at Christian Medical College, Vellore, notes that mismatches between animal models and human disease frequently stall TB drug development. For example, the TB vaccine MVA85A and the drug sutezolid both showed strong results in animals but fell short or remain untested in humans. Linezolid, an approved treatment for multidrug-resistant TB, works but carries significant toxicity.

Current WHO guidelines still recommend standard multidrug chemotherapy, but repurposed host-directed therapies—including metformin, statins, PDE4 inhibitor CC-11050, everolimus, vitamin D, and NSAIDs—are under clinical evaluation. Researchers are increasingly exploring metabolic interventions aimed at the host as a promising strategy.

Singh believes that early-phase clinical trials of meclizine could realistically begin within 3–5 years, under the supervision of the Foundation for Neglected and Tropical Disease Research in Bengaluru.