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New chemical can kill latent tuberculosis bacteria
Date:3/14/2008

rculosis is one of the keys to curtailing or eliminating TB as a disease," Dr. Nathan says. "Antibiotic research has typically focused on killing rapidly dividing bacteria. But with antibiotic resistance rising, that no longer seems like a winning strategy. The long duration of treatment required for curing TB may reflect the fact that some of the bacteria remain non-dividing even during clinically active disease."

With current drugs, it can take six months to eradicate most non-dividing bacteria, and adherence to that long a regimen is difficult for many patients. But if they stop treatment prematurely, drug-resistant bacteria can emerge. Those bacteria are even harder to eradicate if treatment is resumed, and in the meantime, the resistant strain may have also been passed on to others.

In their experiments, the Weill Cornell researchers focused on a bacterial enzyme called dihydrolipoamide acetyltransferase (DlaT). "DlaT's main job is to help M. tuberculosis get energy from nutrients. But when the bacterium is under stress, it also uses the enzyme to defend itself against oxidative damage from human immune cells, such as macrophages," explains study lead author Dr. Ruslana Bryk, assistant research professor in the Department of Microbiology and Immunology at Weill Cornell Medical College.

The team's work in guinea pigs revealed that DlaT is crucial to triggering active TB disease. "So we screened 15,000 compounds to find chemicals that might inhibit DlaT," Dr. Bryk says. The researchers discovered one such compound from a class of chemicals called rhodanines. Their collaborators at deCODE Chemistry then synthesized over 1,000 different variants until the Weill Cornell team found several that can enter and selectively kill non-dividing M. tuberculosis.

"We believe that these DlaT inhibitors probably target additional mechanisms that non-dividing M. tuberculosis needs to survive, and we are currently investigating that possibil
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Contact: Andrew Klein
ank2017@med.cornell.edu
212-821-0560
New York- Presbyterian Hospital/Columbia University Medical Center
Source:Eurekalert

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