Tuberculosis (TB) remains stubbornly difficult to treat not because antibiotics are weak, but because the bacterium learns to survive inside the body’s own immune cells. A new study published in Nature Communications suggests that instead of only hunting for stronger antibiotics, rewiring the metabolism of infected immune cells may hold the key to shortening TB treatment and improving outcomes.
Why TB bacteria survive despite powerful drugs
The bacterium “Mycobacterium tuberculosis” (Mtb) infects macrophages — immune cells designed to engulf and destroy pathogens. Rather than being killed, Mtb creates a protected niche inside these cells, where it can persist for months or even years. This ability to tolerate antibiotics explains why TB treatment typically lasts six to nine months, increasing the risk of poor adherence, toxicity, and drug resistance.
Metabolism inside macrophages shapes bacterial fate
Macrophages kill microbes partly through oxidative stress — bursts of reactive molecules that damage bacterial components. The study found that not all macrophages behave the same way. Some rely mainly on oxidative phosphorylation (OXPHOS), where mitochondria generate energy using oxygen. Others shift to glycolysis, which breaks down glucose for rapid energy production.
This metabolic choice matters. Macrophages dominated by glycolysis experience higher oxidative stress, pushing Mtb into an oxidised state that makes it more vulnerable to anti-TB drugs. In contrast, OXPHOS-driven macrophages maintain lower oxidative stress, allowing Mtb to neutralise damage and tolerate antibiotics.
How TB reshapes its cellular neighbourhood
The research showed that infection does not only affect the macrophages that directly harbour bacteria. Signals from infected cells metabolically reprogram neighbouring, uninfected macrophages as well. This creates a broader microenvironment that can either suppress or enhance the effectiveness of TB drugs, highlighting how deeply infection alters host biology.
NRF2: protector of cells, ally of bacteria
A central regulator linking macrophage metabolism to bacterial survival is NRF2, a protein that boosts antioxidant defences. Macrophages with high NRF2 activity tend to favour OXPHOS and low oxidative stress, creating a drug-tolerant niche for Mtb. When NRF2 was inhibited in experiments, oxidative stress rose, macrophages shifted towards glycolysis, and previously tolerant bacteria became sensitive to isoniazid, a frontline TB drug.
This finding challenges conventional wisdom: a molecule usually considered protective for host cells may inadvertently help TB bacteria survive treatment.
An old drug finds a new purpose
Instead of designing new antibiotics, researchers tested whether existing drugs could reprogram macrophage metabolism. Meclizine — an inexpensive, widely used anti-nausea drug — is known to shift cells from OXPHOS towards glycolysis. In infected macrophages, meclizine increased oxidative stress and sharply reduced Mtb’s drug tolerance.
In a mouse model resembling human TB, combining meclizine with isoniazid led to a roughly 20-fold reduction in bacterial load compared to antibiotics alone. Importantly, treated lungs also showed signs of tissue recovery, a crucial benefit given that many TB survivors suffer lasting lung damage.
Why host-directed therapy matters for TB control
Host-directed therapies work by strengthening or reshaping the body’s response rather than directly killing bacteria. This approach reduces the selective pressure that drives antibiotic resistance. As antimicrobial resistance in TB rises globally, such strategies could act as powerful adjuncts to existing drug regimens.
Because meclizine crosses the blood–brain barrier, it may also help improve treatment of TB forms that affect the central nervous system, where many antibiotics struggle to reach effective concentrations.
What to note for Prelims?
- TB bacteria survive inside macrophages by tolerating oxidative stress.
- Macrophage metabolism (OXPHOS vs glycolysis) influences drug sensitivity of Mtb.
- NRF2 is a key regulator linking host metabolism and bacterial survival.
- Meclizine is an example of host-directed therapy repurposed for TB.
What to note for Mains?
- Explain how host cell metabolism can influence infectious disease outcomes.
- Discuss the limitations of antibiotic-centric approaches in TB control.
- Evaluate the potential of host-directed therapies in addressing antimicrobial resistance.
- Link TB treatment innovations with India’s broader public health goal of TB elimination.
