NIAID program targets drug-resistant TB

SRI International recently began a tuberculosis preclinical drug evaluation program in partnership with the National Institute of Allergy and Infectious Diseases.

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MENLO PARK, Calif.—SRI International recently began a tuberculosis preclinical drug evaluation program in partnership with the National Institute of Allergy and Infectious Diseases (NIAID). The new program is part of the $56.9 million contract the NIH unit first awarded to SRI in 2006 to provide preclinical services for the development of drugs and antibodies as treatments for TB and other infectious diseases such as avian flu, SARS, West Nile virus and hepatitis, as well as biodefense pathogens and toxins.

"Under the larger contracts, we have conducted over 30 different preclinical development tasks, but these are all proprietary and we can't discuss specifics at this time," states Jon Mirsalis, Ph.D., biosciences managing director at the nonprofit research and development organization. "The TB screening portion of this program has just been initiated, so we are only now beginning to receive compounds to test," Mirsalis adds.

"We are using a well established 96-well liquid plate format that uses the redox agent resazurin that changes color when growth occurs," says Kristien Mortelmans, Ph.D., director of the microbiology program in SRI's biosciences division.

Compounds will be tested initially at one concentration with M. tuberculosis (Mtb) H37Rv. Compounds that elicit antimycobacterial activity will be further tested in an expanded dose range to determine the minimum inhibitory concentration (MIC) of compounds that inhibit growth. Compounds with a low MIC value will be further evaluated in other Mtb strains including drug sensitive and multi-drug resistant (MDR and XDR) Mtb strains obtained from different regions in the world. SRI has the capability to test up to 30,000 compounds per year against TB strains.

"Innovative approaches to TB treatment are needed now, as new TB cases increase and Mtb bacteria become increasingly drug-resistant," Mortelmans notes. "This project and our partnership with NIAID will help us find new cures to save lives and further SRI's mission to help solve important global health problems."

As part of SRI's strategic expansion of its TB research program, Dr. Sidharth Chopra recently joined SRI's microbiology program. "Dr. Chopra brings to the table new insights in the behavior of M. tuberculosis inside macrophages that hopefully will lead to the discovery of drugs with new mechanisms of action," Mirsalis says.

TB is considered a global health threat, with one-third of the world's population infected by the TB bacterium. In 2005, TB caused 1.6 million deaths. Strains that are resistant to a single drug are found in every country surveyed by the WHO.

XDR-TB was first widely publicized following the report of an outbreak in South Africa in 2006 where 52 of 53 patients infected with XDR-TB and taken to a rural hospital in KwaZulu-Natal died. The median survival from sputum specimen collection to death was only 16 days. This was the first epidemic for which the acronym XDR-TB was used. Since the initial report in September 2006, XDR-TB has been identified in 49 countries. DDN

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