DOCKING ANALYSIS OF PA824
PA-824 is an experimental drug that is undergoing testing as a potential treatment for TB. Like OPC-67683, PA-824 is a nitroimidazole that has demonstrated bactericidal and sterilizing activity against drug-resistant and non drug-resistant TB. PA-824 has also shown activity against both active and latent TB. In a 2002 agreement with the former biotechnology company Chiron, the TB Alliance was granted exclusive rights to develop the drug as a treatment for TB. The TB Alliance is currently carrying out phase II clinical testing on PA-824.
How it works
PA-824 is a nitroimidazole. It is a prodrug, which means it needs to be activated before it becomes effective against TB bacteria. PA-824 is activated by either a bacterial enzyme or a cofactor, which is a compound that binds to a protein. This activation is the reason why PA-824 does not attack human cells. Human cells lack the bacterial enzyme and cofactor needed to convert PA-824 into its active form.
PA-824 kills bacteria by inhibiting the synthesis of certain proteins and cell wall lipids (i.e. fat molecules) that are needed by bacteria for survival. Researchers believe that PA-824 acts this way against replicating, aerobic (i.e. requiring oxygen) bacteria only.
PA-824 is also active against latent TB bacteria. In a latent state, bacteria are anaerobic and either non-replicating or replicating very slowly. In 2008 researchers from the National Institute of Allergy and Infectious Diseases (NIAID) found that PA-824 kills latent bacteria by releasing a gas called nitric oxide (NO), which poisons the bacteria. NO gas is produced naturally by specific immune cells after they engulf TB bacteria; this is one way the body fights TB infection. But this immune response is sometimes not sufficient to eliminate an infection. PA-824 mimics the body’s natural immune response, but it is more specific and only releases the gas upon entering the TB bacteria.
While PA-824 was originally designed to act against active, aerobic bacteria, this NO mechanism explains how PA-824 is also active against latent, anaerobic bacteria. TB bacteria in their latent state are surrounded by immune cells in structures called granulomas. Oxygen levels are low inside granulomas, so these structures are said to have an anaerobic environment. Researchers determined that NO gas is released in greater quantities in an anaerobic environment. Understanding how PA-824 acts against latent bacteria may help investigators design other TB drugs that use this same mechanism in low-oxygen conditions.1