PA 824

PA 824 is an experimental anti-tuberculosis drug. The bicyclic nitroimidazole like molecule PA-824 has a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis.Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism.The respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment. PA-824 recently was shown to be safe, well tolerated, and efficacious at doses of 100–200 mg daily in a dose-ranging study among drug-sensitive, sputum smear–positive, adult pulmonary TB patients