Drug-Induced Nitric Oxide Kills Latent Tuberculosis Bacteria

The experimental bicyclic nitroimidazole pro-drug PA-824, which requires intracellular activation to trigger its biological function, has been found to effectively kill the latent form of the tuberculosis bacterium Mycobacterium tuberculosis.

Control of tuberculosis, which infects nearly one-third of the world's population, requires killing both the active and latent forms of the causative organism, M. tuberculosis. Attacking the latent form has proven to be especially difficult, as drugs that effect the bacteria's metabolism are not of any use.

In the current study, which was published in the November 28, 2008, issue of the journal Science, investigators at the [U.S.] National Institutes of Health (Bethesda, MD, USA) identified an M. tuberculosis enzyme, deazaflavin-dependent nitroreductase (Ddn), that converted PA-824 into three primary metabolites; the major one being the corresponding des-nitroimidazole (des-nitro). Des-nitro metabolite formation generated reactive nitrogen species, including nitric oxide (NO), which killed the bacteria. Since humans have no enzymes equivalent to Ddn, PA-824 has no effect on human cells.

"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,” explained senior author Dr. Clifton Barry, a senior researcher at the National Institutes of Health. "This highly reactive molecule is akin to a bomb blast that kills the bacteria from within.”

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