Unlocking Tuberculosis’s Energy Source: A New Path to Treatment

Researchers have made a significant breakthrough in understanding how Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB), fuels itself during infection. This discovery, published in The EMBO Journal, provides new insights into one of the world’s deadliest infectious diseases and opens avenues for developing more effective treatments.

How TB Bacteria Obtain Energy

Tuberculosis, a lung infection, remains the leading cause of death from an infectious disease globally. A major challenge in treating TB is the bacteria’s ability to enter a dormant state within the lungs, surviving in lipid-rich environments. In these areas, the bacteria feed on fats from damaged cells, increasing their tolerance to antibiotics and making them harder to eradicate. Long treatment courses, often lasting six months to a year, and challenging side effects contribute to inconsistent patient adherence.

The Role of EtfD

The research team at The Hospital for Sick Children (SickKids) focused on a protein called EtfD, which Mycobacterium tuberculosis uses to extract energy from lipids. They determined the first detailed 3D structure of EtfD and developed a laboratory test to directly measure its activity. This provides researchers with essential tools for early-stage drug discovery targeting this crucial metabolic pathway.

“By providing both a structural model and an assay for EtfD, we now have a toolkit to commence addressing a system that slows down treatment and helps the bacterium develop resistance to antibiotics. This is the first step toward developing better and shorter treatment regimens for tuberculosis,” explains Dr. John Rubinstein, Senior Scientist in the Molecular Medicine program at SickKids and senior author of the study.

EtfD: A ‘Wire’ for Energy Transfer

Using high-resolution cryo-electron microscopy, the researchers found that EtfD functions like a “wire,” transferring energy released from broken-down lipids into the system the bacterium uses to produce adenosine triphosphate (ATP). ATP is the molecule that powers the bacteria’s survival during infection.

Toward More Effective TB Treatment

The newly developed biochemical assay allows researchers to observe EtfD in real-time, determining when the energy pathway is active or blocked. This is crucial for screening potential inhibitors. Knowing the atomic structure of EtfD also helps pinpoint where compounds could bind and improve drug candidates.

Collaborative perform with the SPARC Drug Discovery Facility is underway to test libraries of compounds that could block EtfD’s activity. The availability of both the assay and the structural model will accelerate the identification of compounds that could shorten TB treatment duration.

“TB has been with humanity for thousands of years. With drug-resistant strains on the rise, understanding and targeting its survival strategies is essential if we are going to develop the next generation of TB treatments that give clinicians the best possible tools to support their patients,” adds Dr. Rubinstein.

Source: The Hospital for Sick Children