IN-VIVO SELECTION OF A POPULATION OF TRYPANOSOMA-CRUZI AND CLONES RESISTANT TO BENZNIDAZOLE

A benznidazole-resistant population of Trypanosoma cruzi, Y strain, wa s selected after 25 successive passages (8 months) in mice treated wit h a single high drug dose. Initially, the resistant parasites produced a low parasitaemia level and low mortality rate in infected mice. The reafter, the parasitaemia level and mortality rate increased to the sa me value obtained for mice infected with the wild-type strain. Long-te rm treatment with benznidazole (100 mg/kg/day) cured 71-80% of mice in fected with the wild-type strain. No cure was observed in mice infecte d with the selected resistant parasite population. Treatment with 500 mg/kg of benznidazole at peak parasitaemia cleared all blood parasites from mice infected with wild-type parasites. No effect on parasitaemi a level was observed in mice infected with the selected parasites. Ben znidazole-resistant parasites showed cross-resistance to different dru gs. Contrary to wild type, all clones analysed from the resistant T. c ruzi population were resistant to benznidazole. Without drug pressure the resistance phenotype of clones was far more stable than that prese nted by the resistant population. This work demonstrates, for the firs t time, the in vivo selection of a population and clones of T. cruzi r esistant to benznidazole, and makes available an experimental model fo r the study of mechanisms of drug resistance in T. cruzi.