Grant: Project Grant - PA: Pandemic Preparedness and Health Emergencies Research

Tuberculosis (TB) is a contagious respiratory disease of the lung caused by inhaling the bacterium Mycobacterium tuberculosis (Mtb), and until the 2020 coronavirus pandemic, was the leading causes of infectious disease-related deaths worldwide. Inhaled Mtb are engulfed by immune cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to disable their killing ability, allowing the bacteria to remain hidden from the immune response and protected from drug therapy while inside these cells. By targeting host cell proteins rather than the bacterium itself, host-directed therapy offers unique promise as an alternative treatment for TB. Indeed, boosting host immunity to TB will circumvent the development of antibiotic resistance and the need for drugs to penetrate the impermeable Mtb cell wall. We have identified four key host proteins that are exploited by Mtb to shut down the killing function of macrophages, which provides novel and tangible drug targets to boost immunity to TB. Importantly, we have developed new compounds with excellent activity and safety profiles that can target host proteins to enhance the ability of our macrophage to kill Mtb. As such, this application seeks to progress novel compounds and host targets into the clinical development stream by conducting preclinical, pharmacological, animal, and mode of action studies, which will ultimately advance host-directed therapies aimed at eliminating TB.