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NIAID researchers show how promising TB drug works

Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have determined how a promising drug candidate attacks the bacterium that causes tuberculosis (TB). Published online this week in Proceedings of the National Academy of Sciences, the finding may help scientists optimize the drug candidate, PA-824, which targets Mycobacterium tuberculosis (M. tb).

"PA-824, now in early stage clinical trials, holds promise for shortening the TB treatment regimen, which is currently cumbersome and lengthy," says NIAID Director Anthony S. Fauci, M.D. "This new finding will allow a streamlined approach for making improved versions of the drug."

"Previously, we were flying blind in trying to optimize PA-824 in a rational way because we didn't know which M. tb protein was the target of PA-824's action," says NIAID scientist Clifton Barry, III, Ph.D., who headed the research team.

In preclinical testing, PA-824 showed evidence of being effective against both actively dividing and slow-growing M. tb, giving rise to optimism that the compound may be useful in treating both active and latent TB. (For information about the first clinical trial of PA-824, see June 14, 2005, NIAID press release: http://www3.niaid.nih.gov/news/newsreleases/2005/tb_pa_824.htm.)

PA-824 must be chemically activated in the bacterium before it exerts its anti-tubercular effect, notes Dr. Barry. Earlier research had sketched out the first few steps in this process, but Dr. Barry and his colleagues wanted to pinpoint the precise protein that binds PA-824 and transforms it into a lethal molecule for TB.

The scientists approached the problem indirectly by searching for M. tb mutants that resisted the killing power of PA-824. The team confirmed previous research suggesting that resistance usually occurs when M. tb lacks components
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Source:NIH/National Institute of Allergy and Infectious Diseases


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