Rewiring macrophage metabolism may shorten TB treatment: study, Pg11

Key Highlights:

• Researchers have found that rewiring macrophage metabolism could shorten tuberculosis (TB) treatment by making the bacteria more susceptible to antibiotics.
• The study, published in Nature Communications, suggests targeting host macrophages rather than developing new antibiotics to combat Mycobacterium tuberculosis (Mtb).
• Mtb manipulates macrophage metabolism to create a niche that allows it to tolerate antibiotics, leading to lengthy treatment regimens and drug resistance.
• The researchers identified NRF2, a regulatory molecule, that supports a drug-tolerant niche for Mtb by maintaining high OXPHOS and low oxidative stress conditions.
• The drug meclizine can steer Mtb-infected macrophages towards glycolysis, increasing oxidative stress and lowering the bacteria's tolerance to frontline anti-TB drugs.
• In a mouse model, combined treatment with isoniazid and meclizine resulted in a 20-fold decrease in bacterial load.

Detailed Insights:

• Macrophages, which are immune cells meant to destroy bacteria, are infected by Mtb, which then creates a protected environment inside them.
• Mtb cells with a greater ability to counter oxidative stress are more drug-tolerant than those with weaker defenses.
• Macrophages with reduced Mtb rely on oxidative phosphorylation (OXPHOS), while those with oxidised Mtb have higher glycolysis.
• Inhibiting NRF2 increases oxidative stress and shifts macrophages towards glycolysis, making previously tolerant bacteria more susceptible to isoniazid.
• Meclizine spikes oxidative stress and glycolytic activity in infected macrophages, dramatically lowering Mtb’s tolerance to frontline anti-TB drugs.
• Host-targeting compounds that switch macrophage metabolism to a drug-susceptible state can synergize with conventional anti-TB drugs.
• Therapies targeting host cells offer a promising approach as adjunctive anti-TB therapies, especially given the rising incidence of antimicrobial resistance in Mtb.

Scientific/Technical Concepts Involved:

• Macrophages: Immune cells that engulf and destroy pathogens and cellular debris.
• Mycobacterium tuberculosis (Mtb): The bacterium that causes tuberculosis (TB) in humans.
• Oxidative Phosphorylation (OXPHOS): A metabolic pathway that uses oxygen to generate energy in mitochondria.
• Glycolysis: A metabolic pathway that breaks down glucose to produce energy, occurring in the cytoplasm.