Pyrazinamide Analogs

Chemical Class:
Pyrazinamide/nicotinamide analogs
Pyrazinamide (PZA) is a first-line drug for the treatment of TB that enabled the shortening of treatment of drug-sensitive TB from 9 to 6 months when it was introduced. PZA is unique among TB drugs that are currently available. It demonstrates impressive sterilizing activity and synergy with other drugs in animal models of TB but its activity itself is not potent against M.tb in a test tube. This phenomenon is not well understood. Further, despite extensive study, its mode of action is not fully understood although activation by an enzyme within the M.tb is required for activity. With growing resistance to PZA, work is underway to find the next generation of this drug. PZA must also be administered at a high dose to work effectively. Still, this drug is so powerful that it continues to be used in potential future TB regimens. The PZA analogs program, in collaboration with Yonsei University, seeks to identify a molecule structurally similar to PZA with similar sterilizing activity and synergy with other drugs but that can overcome PZA resistance. Compounds have been identified that synergize with other TB drugs in a mouse model similar to PZA.