'Nitrogen bomb' behind new drug attack on dormant TB
27 November 2008
Around a third of the world’s population have latent or dormant TB, in which the Mycobacterium tuberculosis bacteria are present but not actively dividing. Though infected, they do not display any of the symptoms of TB. However, around ten per cent of these patients go on to develop active TB.
There are currently no drugs available that specifically target latent TB infection. However, one drug in development, PA-824, is effective against latent TB, though scientists did not know how exactly.
Now, a paper published in Science reveals that the key event is the production of nitric oxide gas. “This highly reactive molecule is akin to a bomb blast that kills the bacteria from within,” says Dr Clifton E Barry of the National Institute of Allergy and Infectious Diseases (NIAID) in the United States, who led the research.
Nitric oxide is produced naturally by immune system cells after they engulf bacteria. This is one way that people with healthy immune systems can contain TB infection. But this natural immune response is not always enough to completely rid the body of the bacteria. PA-824 acts in a similar way to the immune cells, but the drug’s effect is more specific and is triggered only after it enters the bacteria.
The researchers observed that for PA-824, generation of nitric oxide is greatest at lower oxygen levels - conditions created by the immune cells when they wall off bacteria. This suggests how PA-824 may help to fight against the non-dividing TB bacteria characteristic in the latent disease.
The study also revealed that, although PA-824 was originally designed to work best under oxygenated conditions, the drug is able to work in low oxygen conditions thanks to the interaction of a bacterial enzyme, Ddn, and a bacterial cofactor.
This has the added bonus of not harming human cells, since humans have neither the bacterial cofactor nor any enzymes equivalent to Ddn.
Conversely, many bacteria have enzymes in the same family as Ddn. Barry says this could lead to new kinds of drugs that generate nitric oxide and interact with the enzymes in other disease-causing bacteria.
Barry’s team is now working to design drugs with a chemical structure similar to PA-824 but optimised to behave best under low-oxygen conditions, in collaboration with the Novartis Institute for Tropical Diseases in Singapore and the Genomics Institute of the Novartis Research Foundation in San Diego.
The research was supported through the Grand Challenges in Global Health Programme, jointly funded by the Wellcome Trust and the Bill & Melinda Gates Foundation.
Image: Mycobacterium tuberculosis in a sputum smear, stained using fluorescent acid-fast stain; CDC/Ronald W Smithwick
References
R Singh et al. Bicyclic nitroimidazoles are intracellular NO donors and kill non-replicating Mycobacterium tuberculosis. Science, 28 November 2008.