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

Abstract

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 molecular weight of the native protein was 125,000 and the protein appeared to contain both dihydropteroate synthase and 6-hydroxymethyl-dihydropterin pyrophosphokinase activities. The sulfonamide class of compounds vary in inhibitory potency by more than three orders of magnitude. Sulfathiazole, sulfamethoxazole, and sulfamethazine, with 50% inhibitory concentrations (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 organisms. The qualitative and quantitative relations among the inhibitors 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 toxoplasmosis. (J. Clin. Invest. 1990. 85:371-379.) antimetabolites.enzymology-protozoan * sulfonamides

The Continuing Challenges of Leprosy

“…Furthermore, there is essentially no dissemination of infection. In athymic nu/nu mice, however, local footpad multiplication of M. leprae appears to be unimpeded, reaching 10 10 or more bacilli per footpad. Histopathologically, the infected footpad tissue becomes an enormous foreign body-type macrophage (M) granuloma, or leproma, and the cells are engorged with bacilli (61) (Fig.…”

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

“…Dapsone and pyrimethamine have been active against both organisms in vitro and in murine models [15][16][17]; therefore, this combination was chosen for evaluation as combined prophylaxis for PCP and toxoplasmic encephalitis. Low cost and the potential for once-weekly administration [18] are additional attractive features of the dapsone/ pyrimethamine combination.…”

Cloning, sequence analysis, and overexpression of Escherichia coli folK, the gene coding for 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase

“…Okinaka and Iwai (24) reported that the HPPK activity in pea seedlings was associated with a multifunctional enzyme of 180,000 Da. HPPK from Pneumocystis carinii and Toxoplasma gondii have also been suggested to be a part of large multifunctional protein (1,36).…”