Researchers at The Hospital for Sick Children (SickKids) have uncovered how the bacteria that\u00a0causes\u00a0tuberculosis\u00a0fuels itself during infection,\u00a0providing\u00a0new insights into one of the world’s deadliest infectious diseases.\u00a0<\/p>\n
The study,\u00a0published in\u00a0The\u00a0EMBO Journal, provides the first detailed 3D structure of a protein called\u00a0EtfD, which the bacterium\u00a0Mycobacterium tuberculosis\u00a0uses to extract energy from lipids (fats), along with the first laboratory test capable of directly measuring its activity. Together, these advances are giving researchers tools to begin early-stage drug discovery focused on this essential metabolic pathway.\u00a0<\/p>\n
“By providing both a structural model and an assay for\u00a0EtfD, we now have a toolkit to begin addressing a system that\u00a0slows down treatment and\u00a0helps the bacterium develop resistance to antibiotics. This is the first step toward developing better and shorter treatment regimens for tuberculosis,” says Dr.\u00a0John Rubinstein, Senior Scientist in the\u00a0Molecular Medicine program\u00a0at SickKids and senior author on the paper.\u00a0<\/p>\n
How TB bacteria turn lipids into energy\u00a0<\/p>\n
Tuberculosis\u00a0(TB), an infection that primarily affects the lungs, is the most common cause of death by infectious disease worldwide. Drug\u2011resistant strains are rising, partly because of the ability of TB bacteria to enter a dormant state and survive for\u00a0long periods\u00a0within lipid\u2011rich areas\u00a0it creates in\u00a0the lung. There, the bacteria feed on lipids from damaged cells for energy, becoming more tolerant to\u00a0any\u00a0antibiotics\u00a0it is exposed to\u00a0and harder to kill.<\/p>\n
Long courses of medication that can last six months to a year or more, combined with difficult side effects, can make it challenging for patients to take their medication consistently.\u00a0<\/p>\n
Using high\u2011resolution cryo\u2011electron microscopy at the\u00a0Nanoscale Bomedical Imaging Facility,\u00a0the research team led by Rubinstein and first author Gautier\u00a0Courbon\u00a0produced the first structural model of\u00a0EtfD.\u00a0<\/p>\n
The structure reveals that\u00a0EtfD\u00a0acts like a wire, moving energy released from broken\u2011down lipids into the system the bacterium uses to produce adenosine triphosphate (ATP), the molecule that powers its survival during infection.\u00a0<\/p>\n
Toward\u00a0more effective TB treatment<\/p>\n
As part of the study,\u00a0Courbon\u00a0also developed the first biochemical assay that can measure\u00a0EtfD\u00a0activity.\u00a0Although\u00a0EtfD\u00a0had\u00a0previously\u00a0been proposed as a promising target,\u00a0including by co\u2011authors Drs. Sabine\u00a0Ehrt\u00a0and Dirk\u00a0Schnappinger\u00a0at\u00a0Weill Cornell Medicine, researchers lacked a way to measure its activity.\u00a0<\/p>\n
“The assay finally lets us see\u00a0EtfD\u00a0working in real time. It shows us when this wire\u2011like pathway is active and when it is blocked, which is essential for screening inhibitors,” says\u00a0Courbon, a PhD Candidate in the\u00a0Rubinstein Lab. “Knowing what\u00a0EtfD\u00a0looks like at the atomic level also helps us\u00a0pinpoint\u00a0where a compound could bind and\u00a0how we might\u00a0improve\u00a0potential\u00a0drug candidates.”\u00a0<\/p>\n
Early collaborative work with the\u00a0SPARC Drug Discovery Facility\u00a0will soon begin to test\u00a0libraries of potential compounds\u00a0that could block\u00a0EtfD.\u00a0<\/p>\n
With the assay and the structure now available to research teams, this\u00a0study\u00a0highlights how structural biology and the Molecular Medicine program at SickKids is helping lay the foundation for\u00a0identifying\u00a0compounds that may one day help shorten treatment duration.\u00a0<\/p>\n
“TB has been with humanity for thousands of years. With drug\u2011resistant 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 Rubinstein.\u00a0<\/p>\n
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