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New compound excels at killing persistent and drug-resistant tuberculosis
Date:6/17/2013

/i> (Mtb)also happens to be unusually well adapted for persisting in humans. Among other strategies, it frequently reverts to a dormant, non-replicating state and also creates attack-resistant cell colonies called biofilms, which contain a high proportion of non-replicating TB.

Compared to ordinary, fast-replicating TB, these other forms of TB are much less susceptible to existing drugs. Effective TB therapy thus requires months to years of regular dosing. But many patients quit before completing such long courses of treatment and end up incubating drug-resistant TB strains. Some strains are now "extensively drug-resistant" (XDR) and virtually untreatableand usually fatal.

Killing the Persisters

"The big challenge here has been to find a drug that clears TB infection more quickly, which means it has to be effective against both replicating and non-replicating TB," said Wang, now also a scientist at the California Institute for Biomedical Research (CALIBR), a non-profit organization founded by Schultz for the early-stage development of new medicines.

Most existing TB drugs work poorly against non-replicating TB, having been developed principally for their ability to kill actively replicating TB. Wang therefore set up a different kind of screening testone to detect compounds that block TB's persistence-related ability to form biofilms.

Because experiments with live TB require a special (level 3) biosafety facility, Wang used a related but non-disease-causing mycobacterium for his initial, high-throughput test. Screening a diverse library of 70,000 compounds, he quickly found one, dubbed TCA1, that stood out for its ability to inhibit mycobacterial biofilms.

Tests in Jacobs's biosafety level 3-certified laboratory confirmed that TCA1 also has powerful activity against TB. "Surprisingly, it turned out to kill both non-replicating and replicating TB," Wang said.

In cell culture tests, TCA1 on it
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Contact: Mika Ono
mikaono@scripps.edu
858-784-2052
Scripps Research Institute
Source:Eurekalert

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