Probing the novel mechanism of action of tuberculocidal compounds

About This Grant

Abstract Tuberculosis (TB) is once again the leading cause of death from infectious disease. Ending the TB pandemic requires new drugs that can sterilize recalcitrant persister cells. Current TB treatments are complex, lengthy and have undesirable side effects. As a result, cases of multi-drug resistant and extensively-drug resistant TB are on the rise. Compounding this problem of rising drug resistance is the notable lack of innovation in drug discovery; new antibiotics are often chemically similar, target the same few bacterial pathways (e.g. cell wall, nucleic acid and protein synthesis) for which mechanisms of resistance are well established, and are slow to come to market. Therefore, the discovery of chemically distinct therapeutics that act via novel mechanisms is necessary to overcome the emergence of resistant strains. Further, drug repurposing represents an attractive option to mitigate cost, time and safety risk associated with antibiotic development. We have identified a molecule (TI-507), initially discovered as a human sphingosine kinase inhibitor, that is active against Mycobacterium tuberculosis (Mtb) with an IC50 of 22 μM, kills persister cells and sterilizes cultures within 4 weeks. Preliminary data suggests that this molecule works through a novel Mtb target, NAD kinase (PpnK), which is essential and involved in many critical cellular processes. Further, TI-507 has a distinct chemical structure and drug-like properties, thereby addressing the major hurdles plaguing antibiotic drug development. While PpnK is thought to be a promising therapeutic target, little is known regarding the biological consequences of PpnK inhibition in Mtb. As such, this proposal has been divided into two specific aims. Aim 1 is focused on target validation and understanding the importance of PpnK inhibition in the context of environmental stress, an intracellular infection model and a murine infection model. Aim 2 focuses on early structure-activity work intended to probe and improve the molecule's anti-tubercular activity. We believe the proposal is providing an innovative approach to develop new therapeutic avenues to treat Mtb infections, which is an urgent unmet need.