| STUDY |
Compounds called nitroimidazopyrans (NAPs) show potent activity against all known forms of tuberculosis, according to preclinical results published last week. If successfully developed into drugs, these compounds could change the way the war against tuberculosis is fought. Treatment options are running out as more strains emerge that resist current therapies. The nature of Mycobacterium tuberculosis, the organism that causes tuberculosis, makes treatment complicated. Drugs currently used to treat susceptible strains are affordable but attack only replicating bacteria. Because M. tuberculosis can persist in a nonreplicating state, treatment takes at least four months. When patients drop out of the lengthy therapy, multi-drug-resistant (MDR) strains evolve. With MDR strains, treatment time and cost escalate to at least two years and as much as $250,000 per patient. The antitubercular potential of NAPs was elucidated by researchers at Co., the University of Washington; Texas A&M University, College Station; the Public Health Research Institute, New York City; and the National Institute for Allergy & Infectious Diseases, Bethesda, Md. The most promising drug candidate, PA-824, was identified from more than 300 3-substituted NAPs. Other promising candidates could emerge from further modifications of the NAP core. Like current antituberculosis drugs, NAPs must first be activated. However, unlike current drugs, which are activated by oxidation, NAPs are activated by reduction. They then inhibit synthesis of a specific lipid in the cell wall of M. tuberculosis and protein synthesis. Current front-line drugs, such as isoniazid, also target cell-wall lipid biosynthesis, whereas many second-line drugs, which are less preferred because of side effects, inhibit protein synthesis. Author believes the bactericidal effect is due more to the action on protein synthesis than to the effect on cell-wall lipid biosynthesis. The researchers found that PA-824 acts specifically against M. tuberculosis. So there is no chance that the organism would develop resistance to PA-824 as a result of the compound's being used to combat other infectious diseases. In addition, development of resistance against PA-824 is about as likely as it is against isoniazid, which has been around since the 1950s but is still useful. And because PA-824 doesn't act on the same targets that current drugs do, "the odds are that we won't encounter strains that have already developed resistance to this compound, because they haven't seen it before," he says. PA-824 is readily prepared from commercially available starting materials in five steps. That should make it "very competitive with current tuberculosis therapeutics |
| UPDATE | 06.00 |
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