at al. Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase

Toxoplasma gondii is a common protozoan disease that often causes life-threatening disease, particularly among patients with the acquired immunodeficiency syndrome. This study demonstrates that the dihydropteroate synthase in T. gondii is kinetically distinct from the enzyme characterized from other sources and can be highly purified with a high yield using sequential dye-affinity chromatography. Conditions have been identified that allow for stabilization of the purified enzyme, and its physical characteristics have been elucidated. The mo-lecular weight of the native protein was 125,000 and the pro-tein appeared to contain both dihydropteroate synthase and 6-hydroxymethyl-dihydropterin pyrophosphokinase activities. The sulfonamide class ofcompounds vary in inhibitory potency by more than three orders of magnitude. Sulfathiazole, sulfa-methoxazole, and sulfamethazine, with 50 % inhibitory concen-trations (IC50's) of 1.7, 2.7, and 5.7 MM, respectively, represent the most potent of this class of inhibitors. Several sulfone analogues, including dapsone, were identified as highly potent inhibitors with ICN's < 1 uM. The results of these cell-free experiments were corroborated by investigating the metabolic inhibition produced by the various inhibitors in intact organ-isms. The qualitative and quantitative relations among the in-hibitors were preserved in both the cell-free and intact cell assay systems. These studies suggest that the sulfones may be important therapeutic agents for the treatment of toxoplas-mosis. (J. Clin. Invest. 1990. 85:371-379.) antimetabolites. enzymology- protozoan * sulfonamide