Researchers at The Hospital for Sick Children (SickKids) have revealed how the bacteria that causes tuberculosis provide energy during infection, providing new insights into one of the world’s deadliest infectious diseases.
This research EMBO Journalrevealed for the first time the detailed 3D structure of a bacterial protein called EtfD. Mycobacterium tuberculosis It is used to extract energy from lipids (fats), and the first clinical test to directly measure its activity will also be conducted. These advances provide researchers with the tools to begin early-stage drug discovery focused on this important metabolic pathway.
“By providing both a structural model and an assay for EtfD, we now have a toolkit to begin addressing systems that delay treatment and help bacteria acquire resistance to antibiotics. This is a first step toward developing more effective, shorter-term treatment regimens for tuberculosis,” said Dr. John Rubinstein, senior scientist in SickKids’ Molecular Medicine Program and senior author of the paper.
How Mycobacterium tuberculosis converts lipids into energy
Tuberculosis (TB) is an infectious disease that primarily affects the lungs and is the most common cause of infectious death worldwide. The rise in drug-resistant bacterial strains is due in part to the ability of Mycobacterium tuberculosis to enter a dormant state and survive for long periods within the lipid-rich areas it creates in the lungs. There, bacteria consume lipids from damaged cells for energy, becoming more resistant to the antibiotics they are exposed to and harder to kill.
Long-term medication therapy, ranging from six months to more than a year, combined with difficult side effects, can make it difficult for patients to consistently take the medication.
A research team led by Rubinstein and first author Gauthier Courbon created the first structural model of EtfD using high-resolution cryo-electron microscopy at the Nanoscale Biological Imaging Facility.
The structure reveals that EtfD acts like a wire, transferring energy released from degraded lipids to a system that bacteria use to produce adenosine triphosphate (ATP), a molecule that powers survival during infection.
Aiming for more effective tuberculosis treatment
As part of the research, Courbon also developed the first biochemical assay capable of measuring EtfD activity. EtfD had been proposed as a promising target for some time, including by co-authors Dr. and colleagues, but researchers lacked a way to measure its activity, according to Sabine Ehrt and Dirk Schnappinger of Weill Cornell Medical College.
“With this assay, we can finally see how EtfD works in real time. We can see when this wire-like pathway is activated and when it’s blocked, which is essential for screening for inhibitors,” said Courbon, a doctoral candidate in Rubinstein’s lab. “Knowing what EtfD looks like at the atomic level can also help us identify where compounds might bind and how potential drug candidates can be improved.”
Initial collaborations with the SPARC Drug Discovery Facility will soon begin testing a library of compounds that have the potential to block EtfD.
The study, whose assays and structures are now available to the research team, highlights how structural biology and SickKids’ molecular medicine program are helping to lay the foundation for identifying compounds that may one day help shorten treatment times.
“Tuberculosis has been with humanity for thousands of years. With drug-resistant bacteria on the rise, understanding and targeting TB survival strategies is essential to developing the next generation of TB treatments that give clinicians the best tools to support patients,” Rubinstein added.
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