New Approaches for Development of PcP Therapy

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DESCRIPTION (provided by applicant): Pneumocystis carinii (PcP) remains an important cause of infection in immunocompromised hosts including patients with AIDS. The most widely utilized therapy is trimethoprim-sulfamethoxazole (TMP-SMX). Recent concerns have arisen over development of mutations to the DHPS locus, which mediates sensitivity to SMX. Accordingly, Dr. Cushion proposes new strategies to develop treatments for Pneumocystis based upon a better understanding of the sterol and mitochondrial metabolism pathways as potential targets for therapy. They propose to first identify efficacious compounds which target enzymatic steps in the sterol biosynthetic and mitochondrial pathways of Pc using in vitro viability assay. Under the second aim, they will assess the potential mechanisms of action of these inhibitors on each pathway by analysis of gene expression using macroarrays. In the third aim, they will attempt to identify synergistic combinations of the sterol ad mitochondrial inhibitors within and between these pathways by construction of inhibitor isobolograms. Finally, they will select the most efficacious combinations of agents and evaluate their effects on gene expression again using the macroarray approach.