Toxoplasma gondii: In vivo and in vitro studies of a mutant resistant to arprinocid- N-oxide

The anticoccidial drug arprinocid and arprinocid- N-oxide, a metabolite produced in vivo, blocked the growth of Toxoplasma gondii in human fibroblasts. The more potent arprinocid- N-oxide inhibited growth by 50% at 20 ng/ml while arprinocid inhibited at 2 μg/ml. For both drugs, the host cell was less sensitive than was the parasite. Hypoxanthine did not reverse the antitoxoplasma activity of either drug. We isolated a parasite mutant, R-Ano R-1 that was 16- to 20-fold more resistant to arprinocid- N-oxide than was the wild type RH T. gondii. This mutant was not resistant to arprinocid in vitro. Arprinocid in a daily oral dose of 136 μg regularly protected mice against an otherwise fatal infection with RH T. gondii and 55 μg had some protective effect. However, all mice infected with R-Ano R-1 and treated with 360 μg arprinocid per day died. Since this mutant is fully sensitive to arprinocid, the form of the drug that is therapeutically active in vivo cannot be arprinocid and is likely to be arprinocid- N-oxide.