Anti-TB Drug Discovery: Design, Synthesis, Evaluation, and Mechanistic Studies

Rajshekhar Karpoormath of the University of KwaZulu-Natal in South Africa will test a set of potential anti-TB hit compounds against clinically relevant TB strains, using the results to generate optimized hit compounds for development of new anti-TB drugs. They will screen the potential hits against susceptible, monodrug-resistant, multidrug-resistant, and extensively drug-resistant TB strains as well as other Mycobacterium strains. The screening results will inform structure-based drug design to generate optimized hit compounds. Potential lead hits will be screened again, with the most promising evaluated against intracellular bacteria in macrophages, tested for in vitro cytotoxicity, and evaluated for mechanism of action in bioassays including carbon-isotope tracing metabolomics and an in vitro granuloma assay.