Scientists find more potent anti-TB drugs

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A team of scientists has synthesized two antibacterial compounds that may prove to be significantly more effective against tuberculosis (TB) than isoniazid, the leading anti-TB drug.

One of the compounds called 2-HA, appears to be four times more deadly to TB bacteria than isoniazid, while the other, called 2-OA, proved 10 times more potent, according to a report in the journal Chemistry and Biology.

The scientists are hopeful that, with more work, these compounds or similar ones will help usher in a new era of anti-TB therapy.

A key feature of the new compounds centers on their ability to block several biochemical pathways that are critically important for the survival of TB bacteria.

“In light of multidrug-resistant TB, which is increasing, there needs to be a concerted effort to find several new drugs at one time or find drugs that target two or more key pathways, Dr. William R. Jacobs who was involved in the research told Reuters Health. “These two compounds are our first example of such drugs.”

Isoniazid, the most effective drug for both treatment and prevention of TB, kills mycobacteria by inhibiting biosynthesis of mycolic acid. It does this by targeting a key enzyme called InhA. This makes InhA “an attractive target for further drug design, Jacobs, from the Howard Hughes Medical Institute at Albert Einstein College of Medicine, and colleagues note in their report.

In trying to improve upon isoniazid, Jacobs and colleagues synthesized more than a dozen chemical decoys for InhA and found that 2-HA and 2-OA potently inhibit InhA activity, killing TB bacteria.

The way in which these two compounds work is unique and unexpected, the authors note. They inhibit three different pathways in mycobacteria that are essential for the bacteria’s survival, Jacobs told Reuters Health.

SOURCE: Chemistry and Biology, March 2006.

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