Mutants of Toxoplasma gondii resistant to atovaquone (566C80) or decoquinate.
Mutants of Toxoplasma gondii resistant to drugs that appear to affect the mitochondrial bc1 complex were isolated with the aid of mutagenesis with ethylnitrosourea. Mutant DeqR-1 was > 1,000-fold more resistant to decoquinate than was the wild type but more sensitive to atovaquone (formerly called 566C80). Mutant AtoR-1 was 20-fold more resistant to atovaquone than was the wild type and was also partially cross-resistant to decoquinate. Both drugs rapidly inhibited oxygen uptake by freshly prepared extracellular parasites, and the mutants were resistant to this inhibition. Neither the addition of uracil to the medium nor the use of a mutant of T. gondii with a defect in pyrimidine salvage had a substantial effect on the in vitro anti-parasitic activity of these drugs, suggesting that de novo pyrimidine synthesis was not the major biochemical target of either drug.
Pfefferkorn
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Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03755.
Borotz
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Nothnagel
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D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D053626:Atovaquone; D002478:Cells, Cultured; D003667:Decoquinate / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D016296:Mutagenesis; D009285:Naphthoquinones / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D014122:Toxoplasma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014498:Uracil
D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D003667:Decoquinate; D014498:Uracil; D053626:Atovaquone