Scientists Identify Molecular Target For Tuberculosis Drug Treatment

June 04, 1998

In a study with major implications for improving tuberculosis (TB) treatment, researchers have identified the exact part of the disease-causing microbe that is targeted by isoniazid, the most widely used TB medication.

Tuberculosis now infects some 1.9 billion people worldwide, one-third of the world's population. The World Health Organization projects that in the next decade, 300 million more people will become infected, 90 million will develop tuberculosis and 30 million will die from it. As the number of new cases increases, multi-drug-resistant strains of Mycobacterium tuberculosis have made treatment more and more difficult.

"Tuberculosis cannot be fully controlled with existing medications," says NIAID Director Anthony S. Fauci, M.D. "We desperately need new drugs to combat this worldwide public health problem."

The new findings will allow scientists to understand and predict how certain strains of M. tuberculosis become drug-resistant. The research also has generated a way to screen potential anti-TB drugs very fast, accelerating the pace of drug development.

"With tests based on these findings, we'll be able to screen thousands of anti-TB compounds in an assay that takes only a few minutes, instead of the three weeks required for normal tests," says Clifton E. Barry III, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID). "I think we have the perfect new tool for developing new drugs against TB."

The research was a collaborative project of Dr. Barry's team and NIAID grantee James M. Musser, M.D., Ph.D., and colleagues at the Baylor College of Medicine in Houston, Texas. Their report appears in the June 5, 1998, issue of Science.

Although isoniazid has been widely used to treat people with tuberculosis, until now no one knew exactly how it worked, and why it no longer works on certain TB strains. Dr. Barry and his colleagues discovered that the drug attacks a protein, called KasA, that the bacterium needs to build its cell wall, thus preventing the growth of M. tuberculosis cells. They also found that mutations in the gene that codes for this protein render TB cells invulnerable to the drug, resulting in antibiotic-resistant TB strains.

With the knowledge that KasA is critical to bacterial growth, scientists can work on designing drugs that specifically attack this molecule. They also can devise tests, or assays, to screen new anti-TB drugs for their power to target the KasA protein.

Such tests are already in the works. Through a CRADA (Cooperative Research and Development Agreement), NIAID scientists and researchers at Pharmacopeia in Princeton, N.J., have devised a fast, high-volume method for screening potential anti-TB compounds. Together they plan to test more than 2 million compounds for anti-TB action.

NIAID supports biomedical research to prevent, diagnose and treat illnesses such as AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

Press releases, fact sheets and other NIAID-related materials are available via the NIAID Web site at http://www.niaid.nih.gov.
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NIH/National Institute of Allergy and Infectious Diseases

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