Toxoplasma gondii: the biochemical basis of resistance to emimycin.
Emimycin was a potent and selective inhibitor of the growth and nucleic acid synthesis of Toxoplasma gondii in human fibroblasts. An emimycin-resistant mutant of T. gondii lost the pyrimidine salvage enzyme uracil phosphoribosyltransferase, the same enzyme absent in parasites resistant to fluorodeoxyuridine. The mutant resistant to emimycin was completely cross-resistant to fluorodeoxyuridine. Emimycin was as good a substrate as uracil for the uracil phosphoribosyltransferase of T. gondii. [3H]Emimycin supplied in the medium of cultures with actively growing intracellular parasites was converted to emimycin riboside-5'-phosphate in the soluble pool of T. gondii. All other emimycin analogs of uracil-containing nucleotides were also formed but little emimycin riboside diphosphate-N-acetylhexosamine was found. [3H]Emimycin was not converted to analogs of the cytidine nucleotides. When intracellular T. gondii were treated with a concentration of [3H]emimycin that partially inhibited parasite RNA synthesis, much less [3H]emimycin was incorporated into RNA than would be predicted by the amount of intracellular [3H]emimycin riboside triphosphate.
Pfefferkorn
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Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire 03756.
Eckel
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McAdams
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D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004351:Drug Resistance; D005467:Floxuridine / Q000494:pharmacology; D009696:Nucleic Acids / Q000096:biosynthesis; D010430:Pentosyltransferases / Q000032:analysis; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000378:metabolism; D014498:Uracil / Q000378:metabolism; D019820:Xanthine; D014970:Xanthines / Q000378:metabolism
D000900:Anti-Bacterial Agents; D009696:Nucleic Acids; D011719:Pyrazines; D014970:Xanthines; D005467:Floxuridine; D019820:Xanthine; D014498:Uracil; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; C028402:emimycin