Characterization of a novel histidine phosphotransfer system involved in the virulence of Mycobacterium tuberculosis

About This Grant

New treatments are desperately needed to control the ongoing tuberculosis (TB) pandemic. Newly emergent antibiotic-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB, are hampering control efforts. Mtb is an unusual pathogen with the remarkable ability to cause both acute life-threatening disease and symptomless latent infections that can last a lifetime. It is estimated that 25% of the world has latent tuberculosis, and in 2023 alone, there were more than 8.2 million TB cases and 1.3 million deaths, making Mtb the leading cause of infectious disease world- wide. Mtb is such a successful pathogen partly due to its extraordinary metabolism; part of its virulence stems from the metabolic flexibility to utilize and scavenge a range of nutrients derived from its human host. A fundamental and currently unanswered question regards how the bacterium regulates its metabolism to cause infection. 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 pathogenesis. We have discovered a novel regulatory system that Mtb requires to consume essential energy sources for its survival in the host and to cause disease. Our hypothesis is that Virulence Associated Dikinase (VadK) coordinates metabolism and virulence by interacting with partner proteins. Importantly, VadK also represents a novel drug target. We will test this hypothesis using a combination of biochemistry, structural biology and microbiology. We will investigate how VadK physically and functionally interacts with its partner proteins to gain insights into how this novel histidine kinase system functions, while also unraveling the mechanism of action of VadK.