The finding could help scientists develop ways to treat dormant TB infections, and suggests a strategy for drug development against other bacteria as well.
One-third of the world's population is infected with Mycobacterium tuberculosis (M. tb), the bacteria that cause TB.
In a previous study, lead author Clifton E. Barry, III, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), and his colleagues found that M. tb mutants lacking a specific bacterial enzyme were resistant to PA-824, but at that time, they did not know the function of the enzyme.
"It took several years, but at last we were able to recreate in the test tube what happens inside mycobacterial cells when the bacterial enzyme, which we named Ddn, and a second bacterial component called a cofactor, interact with PA-824," said Barry.
They found that the key event in PA-824 metabolism is the production of nitric oxide (NO) gas.
"This highly reactive molecule is akin to a bomb blast that kills the bacteria from within," he added.
No gas is produced naturally by certain immune system cells after they engulf M. tb or other bacteria. This is one way that people with healthy immune systems can contain M. tb infection.
However, this natural immune response is not always enough to completely rid the body of TB bacteria. In essence, PA-824 performs similarly to the No-producing immune cells, but the drug's effect is more specific and triggered only after it enters the bacteria.
The non-dividing M. tb bacteria characteristic of latent TB infections are walled off by immune cells that aggregate around the bacteria to form a body called a granuloma. Oxygen levels are low inside granulomas.
In the new study, the researchers observed that No-generation during PA-824 metabolism is greatest when oxygen levels are low. This observation suggests how PA-824 may work against non-dividing M. tb. PA-824 was originally designed to work best under aerobic, or oxygenated, conditions.
Barry said that with this new understanding of how the bacterial enzyme and cofactor act on PA-824 under low-oxygen conditions, scientists could design drugs with a chemical structure similar to PA-824 but optimize them from the start to behave best under low-oxygen conditions.
The study is published in the Nov. 28 issue of Science.