Ubiquitin pathway modulators as novel antituberculosis drugs

New approaches are needed to treat NIAID priority pathogens, including Mycobacterium tuberculosis (Mtb). Emerging drug-resistance in Mtb poses a significant threat to global health, generating a pressing need to develop innovative therapeutics with the potential to avoid the rapid evolution of drug resistance. One novel approach is to harness host defense mechanisms to treat both drug-sensitive and drug-resistant tuberculosis (TB). A key observation that may lead to new combination therapies is that we have identified important roles for autophagy (ATG) proteins in resistance to Mtb specifically via degradative autophagy killing the organism. These new findings, in the setting of the extreme medical need for new approaches to treat TB, led to this new SBIR application to fully leverage prior discoveries and to focus on TB and multidrug-resistant (MDR)-TB in response to NIH and public health priorities. As a master regulator of autophagic degradation of mitochondria, Parkin E3 ligase is an important protective factor against Mtb. Parkin E3 ligase promotes clearance of Mtb in macrophage infection models. As such, activation of Parkin is expected to have antituberculosis therapeutic effect. Pogenra’s UbiProTM drug discovery platform was employed to discover novel, potent and selective Parkin activators. We demonstrated that Parkin activators robustly inhibited growth of Mtb in macrophages. In this Phase I grant, we propose evaluate Parkin activators for their antimycobacterial efficacy in cellular and animal models of tuberculosis and perform mechanism of action studies. The ultimate commercial goal of this project is the development of small molecule Parkin activators as novel drugs that could treat tuberculosis.