Efforts Toward the Discovery and Development of Novel Tuberculosis Therapeutics

I. Introduction to Tuberculosis – Current Therapeutics and Unmet NeedsThis chapter provides a brief overview of Tuberculosis and recent efforts to combat it including recent small molecule drugs and host-directed therapies. 4'-Phosphopantethienyl transferase is introduced as an exciting and actionable drug target as well as the concept of preventing macrophage death as a potential host-directed therapy.II. Efforts Toward the Discovery of Phosphopantetheinyl Transferase Inhibitors inMycobacterium tuberculosisThis chapter explores efforts to develop inhibitors of 4’-phosphopantetheinyl transferase (PptT) based on three series of compounds: one based on a previously known amidinourea- based inhibitor, a series in which we attempted to replace the amidinourea with alternative heterocycles, and a series based on the anticancer drug raltitrexed. From these studies, we were successfully able to reduce potential off-target cardiotoxic effects in the amidinourea series, identify 2,6-diaminopyridines as a potential amidinourea bioisostere in the second series, and in the third series based on raltitrexed, while we did not identify a whole-cell active compound, we discovered the most potent PptT reported to date.III. Efforts Toward the Target Identification of Calpain Inhibitor XII in MacrophagesInfected with Mycobacterium tuberculosis iiiThis chapter investigates the biological role of the small peptidic alpha-ketoamide protease inhibitor, Calpain Inhibitor XII (CI-XII). Previous studies have determined that CI- XII is able to prevent the death of macrophages infected with Mycobacterium tuberculosis (Mtb). Further understanding the biological role of this compound has the ability to deepen the understanding of the mechanism behind the death of macrophages infected with Mtb and also to uncover a potential drug target for host-directed therapy. Biotinylated probes were utilized to pull down protein hits, and an iridium conjugated probe was utilized to perform proximity labelling experiments which yielded a short list of potential target candidates.