Reprogramming Macrophages: A New Hope for Tuberculosis Therapy
Why does TB therapy take six-nine months, and why do some Mycobacterium tuberculosis inside macrophages survive antibiotics better than others? Rigorous experiments have now revealed that macrophage’s own metabolism and the host cell where the bacteria live play a key role in shaping drug tolerance
Globally, tuberculosis (TB) causes over a million deaths annually. Despite the availability of effective antibiotics, TB treatment requires at least six months of multidrug therapy, which is much longer than for most bacterial infections. This prolonged treatment is largely due to the ability of Mycobacterium tuberculosis (Mtb) to persist in a drug-tolerant state. These tolerant cells survive antibiotic pressure without genetic mutations, often leading to poor patient compliance and giving the bacteria time to develop antimicrobial resistance (AMR). Over time, this can result in multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB. Consequently, drug-tolerant cells that “wait out” antibiotic exposure contribute to long treatment durations and the risk of relapse with harder-to-treat forms of the disease. Researchers worldwide are now working to unravel the mechanisms of drug tolerance, aiming to develop new therapies that shorten TB treatment and prevent the emergence of MDR/XDR-TB.
In a recent study from our laboratory that was published in the journal Nature Communications, we discovered that TB-causing bacteria develop antibiotic tolerance largely through its ability to infect macrophages — its primary host cells — in specific metabolic states. Our work revealed that macrophages are metabolically heterogeneous: a subset provides a protective niche that shields the bacteria from antibiotics, while others render the bacteria more susceptible. Importantly, we identified meclizine, a safe and widely available FDA-approved anti-nausea drug, as a metabolic modulator that reprograms macrophages to create an environment where M. tuberculosis can no longer tolerate antibiotics. This significantly enhances the efficacy of existing TB drugs, as demonstrated in both macrophage cultures and animal models of experimental TB.
How infection rewires macrophages
When M. tuberculosis infects the lungs, it is taken up by macrophages, the body’s professional “eaters” of microbes. Once inside, the bacterium enters a complex tug-of-war with the host cell. Rather than being destroyed, M. tuberculosis persists and even manipulates the host cell’s defenses in a manner that promotes persistence and drug tolerance.
We isolated macrophages from mouse bone marrow (bone marrow–derived macrophages, BMDMs) and infected them with TB-causing bacteria ex vivo. These experiments revealed that infected macrophages adopt distinct metabolic states: some rely primarily on oxidative phosphorylation (OXPHOS) — a mitochondrial process that efficiently generates energy using oxygen — while others shift toward glycolysis, rapidly breaking down glucose to produce energy in the form of ATP.
We next asked how these distinct metabolic states (OXPHOS vs. glycolysis) influence bacterial tolerance to anti-TB drugs. To probe the physiology of M. tuberculosis residing within metabolically different macrophage subsets, we used a redox-sensitive fluorescent biosensor genetically engineered to express in the bacteria, allowing real-time monitoring of bacterial redox stress.
The results were striking: TB-causing bacteria within OXPHOS-dominant macrophages experienced less stress and maintained a more reduced cytosolic environment, enabling them to neutralize the oxidative stress induced by anti-TB drugs. In contrast, bacteria within glycolytic macrophages were exposed to elevated levels of reactive oxygen species (ROS) — highly reactive molecules produced by dysfunctional mitochondria. Since anti-TB drugs also generate reactive oxygen species, this combined oxidative burden overwhelmed Mtb’s defense capacity, rendering them more susceptible to antibiotics. Thus, the infection does not occur in a uniform environment; instead, diverse metabolic states in macrophages affects bacteria physiology and determines how effectively drugs can kill them.
A hidden regulator: NRF2
To identify the macrophage genetic factors driving these metabolic changes during infection, we compared the gene expression profiles of macrophage subsets infected with drug-tolerant (reduced) or drug-sensitive (oxidized) M. tuberculosis. Using large-scale transcriptomic analysis, one transcriptional regulator emerged as a key player: NRF2.
NRF2 is a master transcription factor that coordinates antioxidant and mitochondrial protection programmes in mammalian cells by activating hundreds of detoxification genes to defend against oxidative stress. During M. tuberculosis infection, however, this protective mechanism appears to benefit the pathogen. We observed strong activation of the NRF2 pathway in macrophages harbouring drug-tolerant (reduced) M. tuberculosis. Suppressing NRF2 activity-either through gene silencing or pharmacological inhibition increased intracellular reactive oxygen species (ROS) levels, driving the bacteria into an oxidised state and making it highly susceptible to isoniazid, a first-line anti-TB drug.
These findings suggest that NRF2-driven antioxidant responses in macrophages create a low-stress environment that inadvertently maintains the bacteria in a reduced redox state, enhancing its ability to tolerate anti-TB drugs.
Changing the macrophage energy flow
We next examined whether deliberate reprogramming of macrophage metabolism could alter the ability of the bacteria to tolerate antibiotics. By blocking the transport of pyruvate — a key glycolytic end product-into mitochondria, we forced infected macrophages to rely less on oxidative phosphorylation (OXPHOS) and more on glycolysis. This metabolic shift increased oxidative stress within macrophages and dramatically reduced drug tolerance in Mtb by inducing excessive reactive oxygen species inside the bacteria.
Conversely, when infected macrophages were cultured in galactose instead of glucose — a condition that promotes mitochondrial OXPHOS — the bacterial population became more reduced and more tolerant to antibiotics. Together, these findings demonstrate that the metabolic mode of macrophages (OXPHOS vs. glycolysis) during infection directly dictates whether intracellular bacteria persist or is eliminated under antibiotic pressure.
Repurposing a common drug: Meclizine
Although these mechanistic insights were promising, the next challenge was to translate them into a practical therapeutic strategy. While many compounds can influence macrophage metabolism, few do so in a controlled and safe manner suitable for human use. We therefore turned our attention to meclizine, an over-the-counter drug widely used to treat motion sickness and vertigo.
Previous studies have shown that meclizine safely shifts mammalian cell metabolism from oxidative phosphorylation (OXPHOS) toward glycolysis without causing toxicity. Consistent with this, treating M. tuberculosis-infected macrophages with meclizine reduced mitochondrial OXPHOS, enhanced glycolytic activity, and increased mitochondrial reactive oxygen species. Microscopy further revealed smaller, fragmented mitochondria — visual confirmation of metabolic reprogramming.
Crucially, the bacteria within meclizine-treated macrophages could no longer maintain the reductive, drug-tolerant state. Clinically used TB drugs such as isoniazid and moxifloxacin became markedly more effective in killing the bacteria. When glycolysis was chemically blocked using 2-deoxyglucose, meclizine’s beneficial effect disappeared, confirming that the drug acts through host metabolic remodelling by inducing glycolysis and ROS generation.
From cells to mice: Meclizine boosts TB therapy
Encouraged by these findings, we next tested whether meclizine could enhance the efficacy of TB drugs in a mouse model that closely mimics human disease. Infected mice were treated with isoniazid, meclizine, or a combination of both for several weeks.
Treatment with isoniazid alone reduced bacterial loads in the lungs, whereas co-administration with meclizine led to an additional twenty-fold decline in viable bacteria. The lungs of meclizine-treated mice accumulated more glycolytic macrophages, showed improved healing with markedly reduced tissue inflammation.
Importantly, pharmacokinetic analyses revealed no adverse drug-drug interactions between meclizine and standard TB drugs such as isoniazid, rifampicin, ethambutol, or pyrazinamide. Given its long history of safe clinical use and favourable pharmacological properties, meclizine emerges as a promising candidate for repurposing as an adjunct therapy to potentially shorten TB treatment.
Implications and the road ahead
Our study uncovers how targeted reprogramming of macrophage metabolism can overcome M. tuberculosis drug tolerance. We reveal a previously underappreciated dimension of tuberculosis biology: the host’s metabolic state is heterogeneous, and this diversity profoundly influences bacterial physiology and antibiotic response.
The efficacy of meclizine in reversing bacterial drug tolerance underscores the promise of host-directed therapy (HDT) — an approach that strengthens the host’s ability to combat infection rather than directly targeting the pathogen. Because meclizine is safe, inexpensive, and already approved for human use, it offers a realistic short-term strategy to improve existing TB regimens. Importantly, since meclizine acts through host metabolic remodelling rather than directly on bacteria, it avoids the risk of driving antimicrobial resistance (AMR). These findings provide a strong rationale for initiating human clinical trials to evaluate the safety and efficacy of meclizine as an adjunct to standard TB therapy.
Future directions include testing this metabolic reprogramming strategy in more advanced infection models and identifying additional modulators capable of “re-educating” immune cells. Beyond tuberculosis, the concept that pathogens manipulate host metabolism for their survival may have far-reaching implications for chronic bacterial, viral, and parasitic diseases.
By learning to harness and reshape cellular energy metabolism, we may finally turn one of M. tuberculosis’ greatest survival strategies i.e. metabolic adaptation into its weakness.
