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.

RNA Polymerase (RNAP) is the enzyme that transcribes genetic information from DNA into RNA, which, in turn, directs the assembly of proteins that carry out most biological functions and are key structural components of cells. RNAP is a proven target for anti-tuberculosis therapies with the uncommon ability to kill both active and dormant M.tb when the enzyme is inhibited. A class of antibacterial compounds known as rifamycins, which also target RNAP, are used as part of the first-line treatment for TB and can rapidly reduce populations of M.tb to undetectable levels.

Macrolides are a diverse family of naturally occurring and semi-synthetic antibiotics that are widely prescribed for treatment of various bacterial infections. They exert their antibacterial activity by inhibiting protein synthesis in pathogenic bacteria. In this program, a proprietary macrolide molecule has been identified that has excellent activity against M.tb and its analogues are being synthesized to improve potency and pharmacokinetics.

In this project, indazole derivatives have been identified to have excellent in vitro and in vivo activities. Their optimization and mechanism of action studies are currently in progress.