The objectives of this contract ar to provide a standardized mechanism for the pre-clinical evaluation of new candidate therapies against Mycobacterium tuberculosis infection. This represents a component of the Division of AIDS' opportunistic infections drug development program and specifically addresses the discovery and development of new therapies to treat tuberculosis, an opportunistic infection which 20 to 30% of HIV patients positive for PPD in the United States are at risk of developing through reactivation of latent infections. Its most common manifestation in AIDS patients is inevitably fatal without appropriate treatment, and may require long-term therapy, i.e. greater than 12 months to lifetime. Treatment-limiting toxicities, lack of potency, and the emergence of resistance have compromised the utility of established drugs. The most significant deficiencies of present therapies are the lack of efficacy against drug resistant strains and the inability to eradicate the latent form of M. tuberculosis which is reactivated when the immune system becomes severely compromised. Specifically, the contractor will evaluate potential therapeutic agents for efficacy against tuberculosis in a mouse model of the infection and will employ defined biologically relevant indicators of disease and infection as endpoints. The test agents will be selected by the Project Officer on the basis of previously determined in vitro activities. The contractor will develop, modify, improve, or otherwise further characterize the animal model or develop other models to expand utility in the evaluation of therapies for the ability to kill quiescent or slowly growing M. tuberculosis. In addition, the contractor will develop alternative models, if necessary, and perform additional studies such as comparison of M. tuberculosis strains and preliminary pharmacokinetic studies. This information will be of benefit to the Government in determining the best candidate therapies for inclusion in clinical trials of new agents against tuberculosis.
