TOXOPLASMA-GONDII - SUSCEPTIBILITY AND DEVELOPMENT OF RESISTANCE TO ANTICOCCIDIAL DRUGS IN-VITRO

Anticoccidial drugs were evaluated for activity and for the developmen t of resistance in a model of Toxoplasma gondii growing in human fibro blast cultures. Of 13 anticoccidial drugs tested, 9 had selective anti toxoplasma activity (50% inhibitory concentration, in micrograms per m illiliter): decoquinate (0.005), arprinocid-N-oxide (0.015), robenidin e (0.03), the aryl triazine CP-25,415 (0.2), toltrazuril (0.4), clopid ol (1), dinitolmide (Zoalene; Dow) (10), and the carboxylic acid ionop hores monensin (0.001) and salinomycin (0.04). Glycarbylamide, amproli um, nicarbazin, and the 6-(p-bromophenoxy)-7-chloro analog of halofugi none (Stenorol; Roussel-UCLAF) (CP-63,567) were toxic for the fibrobla sts. Since Eimeria tenella has a similar drug susceptibility profile, anticoccidial drugs can be viewed as a potential source of new antitox oplasma therapies. The development of resistance has limited the usefu lness of most of these drugs as anticoccidial agents; in coccidia, res istance to all except the ionophores occurs readily in vivo. We explor ed the development of resistance in T. gondii by attempting to select mutants in vitro from parasites mutagenized with ethylnitrosourea. Mut ants that had 20- to 50-fold-reduced susceptibility to decoquinate, ar prinocid-N-oxide, and CP-25,415 were obtained. Ionophore-resistant T. gondii mutants were also selected in vitro; however, there was only a twofold difference in susceptibility between these mutants and the wil d type. For three drugs (clopidol, robenidine, and toltrazuril), we we re unable to select resistant mutants. For experimental anticoccidial drugs, there is currently no in vitro method for assessing the risk of development of resistance in Eimeria species. Our results suggest tha t T. gondii may offer a useful surrogate for this assessment.