The importance of the parasitic protozoa as agents of disease and animals is well recognized. Despite the worldwide prevalence of these diseases, little effort has been expended to eradicate these diseases. This proposal offers a genetic approach to study the biochemical differences between the parasites and their mammalian hosts with the ultimate goal of generating information which could be useful in designing drugs to aid in disease treatment. All the parasitic protozoa studied so far are incapable of synthesizing de novo the purine ring and are therefore auxotrophic for purines. They have evolved a series of unique purine salvage enzymes, not found in mammalian systems, which enable them to scavenge host purines. Presently, it is not known which of these enzymes are physiologically important. The intent of this proposal is to isolate and characterize mutants of one protozoan parasite species, Leishmania donovani, which are resistant to cytotoxic purine analogs and which are deficient or impaired in their utilization of exogenous purines. Comparative biochemical and physiological studies between normal and genetically deficient Leishmania, both in the insect vector and mammalian forms, may lead to the rational design of chemotherapeutic regimens that exploit specific functional metabolic pathways or targets in the protozoan, but which do not adversely affect the mammalian host.