Molecular Genetic Tools for the Identification and Analysis of Drug Targets in Toxoplasma gondii

Abstract

Chemotherapy for acute toxoplasmosis has classically relied on inhibitors of the folate metabolic pathway (Brooks et al. 1987), typically a synergistic combination of sulfonamides (inhibitors of dihydropteroate synthase, which produces folic acid) and inhibitors of dihydrofolate reductase (e.g., pyrimethamine). Unfortunately, the combination of pyrimethamine and sulfonamides has been less successful against toxoplasmic encephalitis associated with acquired immunodeficiency syndrome (AIDS) (Luft and Remington 1992). Chronic treatment must be maintained to guard against the re-emergence of parasites from latent tissue cysts, as the bradyzoite forms are insensitive to most metabolic inhibitors. Long-term sulfonamide administration often produces a severe hypersensitivity response, however, and pyrimethamine alone is usually insufficient to prevent relapse; prolonged pyrimethamine therapy may also result in bone marrow depression (Haverkos 1987; Leport et al. 1988; Tenant-Flowers et al. 1991). Moreover, reliance on chronic treatment raises the fear that drug-resistant parasites may emerge. These concerns have lent renewed impetus to the development of improved treatment protocols, the identification of novel parasiticidal agents, and studies on the metabolism of the parasite, with an eye toward more effective drug therapy (Laughon et al. 1991).