Tuberculosis kills 1.3 million people each year, and the bacterium that causes it, *Mycobacterium tuberculosis*, can switch between causing active disease and lying dormant in the body for decades. Researchers have discovered a protein, named VadK, that the bacterium needs to consume nutrients from human cells and to cause disease. Without it, the bacteria cannot grow in human cells or cause tuberculosis in mice. This project aims to work out exactly how VadK coordinates the bacterium’s metabolism with its ability to cause infection. The researchers will map how VadK interacts with partner proteins, how those interactions control the production of disease-causing molecules, and what happens when the system is disrupted during infection. This is fundamental science—it will not produce a new drug tomorrow. But understanding this regulatory system could reveal vulnerable points in the bacterium’s metabolism that pharmaceutical companies and charities could target with new treatments. The same system also exists in other clinically and industrially important bacteria, so the insights could extend beyond tuberculosis.
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Context It is estimated that 25% of the world has latent tuberculosis, and in 2023 alone, there were more than 11 million tuberculosis cases and 1.3 million deaths, making the causative agent, Mycobacterium tuberculosis the leading cause of infectious disease world-wide. New treatments are desperately needed to increase the effectiveness of current tuberculosis treatments and to combat a rise in antibiotic-resistant strains of M. tuberculosis. Challenge M. tuberculosis has the remarkable ability to cause both acute life-threatening diseases and symptomless latent infections that can last a lifetime. A key to understanding the tuberculosis disease process is M. tuberculosis’ remarkable metabolic flexibility and plasticity that enables it to consume a wide range of human host-derived nutrients. A fundamental and currently unanswered question is how pathogens such as M. tuberculosis coordinate their metabolism to produce the cellular components that cause disease. Answering this question is of therapeutic significance as targeted dysregulation would both starve the bacteria and prevent it from successfully colonizing the human host, effectively killing the bacteria and stalling the disease process. Timeliness We have discovered a unique regulatory protein that is required for M. tuberculosis to consume energy sources essential for its survival in the host and for its ability to cause disease. We have shown that without this protein M. tuberculosis cannot grow in human cells or cause tuberculosis disease in a mouse. Our hypothesis is that this regulatory protein that we have named Virulence Associated Dikinase (VadK), coordinates metabolism and virulence by interacting with protein partners. This project will test this hypothesis by capitalizing on our combined expertise and novel experimental tools in microbiology, biochemistry, and structural biology. Aims and Objectives Our overall objective is to find out exactly how this unique regulatory system works. Exploiting our strong, complementary, and multi-disciplinary expertise we will decipher: The physical determinants of VadK's interactions with its partner proteins How VadK and partner proteins control metabolism and hence the production of genes required to cause tuberculosis. The effect of modulating the VadK system on metabolism and survival during experimental infection. Through this research, we will start to understand the fundamental biology of how M. tuberculosis coordinates metabolism to cause disease. Benefits Through this research we will discover how pathogens link metabolism with virulence that will be of benefit to scientists studying how cells coordinate these activities. We have also identified this system in other clinically and industrially relevant bacteria and this research will guide and inspire future studies in this area. The biology from this project will identify and validate drug targets that can be leveraged by the pharmaceutical industry and charities that are so urgently looking for new approaches to treat tuberculosis. Therefore, this work fits firmly into the MRC remit of understanding human infectious diseases which focuses on tackling global infectious diseases, including tuberculosis, and translating these findings to benefit human health.
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