DprE1 inhibitors were identified by high-throughput screening against mycobacterial whole cells and represent a novel class of compounds as anti-TB agents. DprE1 is an essential mycobacterial enzyme that is involved in the synthesis mycobacterial cell walls. DprE1 is a novel target and as such, these inhibitors are active against M.tb strains resistant to known TB drugs. Several analogues of TCA1 have been shown to have in vivo efficacy in both mouse acute and chronic infection models. Genetic and affinity-based methods identified decaprenyl-phosphoryl-β-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1.