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

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is one of the most devastating infectious agents in the world. One third of the world's population is exposed to Mtb, which kills nearly two million people annually. With the increasing prevalence of drug resistant Mtb, there is a pressing need to develop better and new drugs against this notorious pathogen. A novel drug discovery approach termed Host Directed Therapy (HDT), was proposed recently to overcome drug resistance in treating infectious diseases. Since HDTs do not target the microbe directly but rather assist the host in fighting infection, they would have reduced chances of generating resistance. HDT approaches prevent microorganisms from thriving inside their human host or boost host defence mechanisms that can synergies with antibiotics. During our current CIHR funding, we identified two HDT lead compounds that restrict Mtb growth intracellularly in infected macrophages. These are the FDA approved Parkinson drug Benzotropine and the Glycogen Synthase Kinase 3 beta inhibitor P-4423632. Both compounds are active at low uM concentrations at dose dependent manner and with limited to no toxicity to the host cell. The purpose of this application is to progress these two compounds into clinical development stream by conducting preclinical, animals and mode of action studies.