Toxoplasma gondii: characterization of a mutant resistant to sulfonamides.
Sulfadiazine was a potent inhibitor of the in vitro growth of Toxoplasma gondii, although it had little effect during the first 24 hr of treatment. A mutant parasite (R-SulR-5) with a 300-fold increase in sulfadiazine resistance was selected by a combination of chemical mutagenesis and growth in gradually increased sulfadiazine concentrations. This mutant was completely cross-resistant to several other sulfonamides and to dapsone. The same concentration of p-aminobenzoic acid reversed the sulfadiazine inhibition of both mutant and wild-type parasites even though much higher concentrations of sulfadiazine were used to inhibit the mutant. Dihydropteroate synthase, a sulfonamide-sensitive enzyme in the pathway leading to dihydrofolic acid, had similar activities in wild-type and R-SulR-5 parasites. However, the mutant enzyme was 40-fold more resistant to sulfadiazine and had higher apparent Kms for both substrates, p-aminobenzoic acid and dihydropteridine pyrophosphate. The mutant was slightly less active than the wild type in the uptake of sulfadiazine.
Pfefferkorn
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ER
Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03755.
Borotz
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SE
Nothnagel
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RF
D010129:4-Aminobenzoic Acid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004351:Drug Resistance; D009154:Mutation; D013411:Sulfadiazine / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D013449:Sulfonamides; D013411:Sulfadiazine; D004094:Dihydropteroate Synthase; D010129:4-Aminobenzoic Acid