Host-directed therapies (HDTs) have the potential to significantly enhance current antibiotic regimens for tuberculosis (TB). Macrophages are the major host cell niche for Mycobacterium tuberculosis (Mtb) infection, and apoptosis of Mtb-infected macrophages, which is repressed by Mtb, constitutes an important innate defense mechanism against TB. The goal of this program is to identify clinically-relevant HDTs that maximize apoptosis induction in Mtb-infected macrophages, characterize their mode of action, and determine their potential to shorten the duration of curative treatment for drug-susceptible and drug-resistant TB in an animal model of clinical relevance.