Major objectives of the proposed research are to isolate 100 mg of homogeneous dihydrofolate reductase (DHFR) from Candida albicans, crystallize the enzyme and determine its three-dimensional structure using x-ray diffraction methods. Armed with the resulting detailed knowledge of the geometrical and topographical properties of Candidas DHFR in relation to the known structure of the corresponding vertebrate enzyme, we will endeavor to design specific pharmacologically active inhibitors that selectively cripple the bacterial reductase without interfering with one-carbon metabolism in the host. It is intended that such novel inhibitors will address the current critical need for new anti-infection agents with enhanced anti-Candidal activity against Candida albicans.
