Grant: Project Grant

Tuberculosis (TB) is an infectious lung disease caused by Mycobacterium tuberculosis (Mtb). According to the WHO, TB is the leading cause of mortality from a single infectious agent worldwide. In Canada, TB is a public health crisis among Indigenous peoples. The continued spread of multidrug-resistant (MDR) Mtb is a growing problem. Treatments for these MDR strains are complex, slow, expensive, and are accompanied by severe side effects. These alarming facts demonstrate the urgent need for fundamental research to develop novel TB therapeutic strategies. Here I propose mechanistic studies of the Mtb proteasome machinery which enables the pathogen to evade the immune system of the host. Mtb proteasome-mediated protein degradation is essential for resistance of the pathogen to the host immune system and for the ability of Mtb to cause lethal infections. Thus, Mtb proteasome represents a novel therapeutic target for developing antimicrobials against MDR Mtb. The research proposed in this grant will use a combined nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) approach to study the mechanisms via which dynamics and allostery control the function of Mtb 20S proteasome core particle (CP), its interactions with regulatory particles (RPs), as well as the substrate proteins that it targets. This unique combination of methods overcomes the challenges that the heterogeneity and the size of proteasome machinery represent and enables discovering allosteric hotspots that regulate the proteasome function in vivo. The proposed studies chart a path towards altering the activity of Mtb proteasome using allosteric activity modulators and its inherent conformational plasticity.