The broad, long-term objective of this proposal for a cooperative drug discovery group is to meet the critical and urgent need for discovery of more effective and less toxic drugs and therapeutic regimens and modalities for treatment of toxoplasmosis in AIDS patient. Toxoplasmosis has emerged as a major cause of morbidity in patients with AIDS. Drugs that have proven effective in treatment of toxoplasmosis in AIDS are extremely limited and those most commonly used are frequently associated with drug reactions sufficiently severe to preclude their further use in a given patient. Thus, there is a real need to discover and evaluate new treatment modalities for toxoplasmosis in AIDS patients. The focus of this proposal is directed towards gaining new knowledge for the treatment of toxoplasmosis as it occurs in patients with AIDS. Its scope covers the areas of study of the in vitro and in vivo activity of new agents for treatment of toxoplasmosis and toxoplasmic encephalitis on the tachyzoite, cyst and bradyzoite forms of the parasite; Use molecular genetics in combination with drug resistant mutants to gain an understanding of the target of a given drug's action; and to develop a strategy to interrupt both acute and reactivation of toxoplasmosis based on the necessity of T. gondii motility in host cell invasion and the unique mechanism of parasite movement.
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