A benznidazole-resistant population of Trypanosoma
cruzi, Y strain, was selected after 25 successive passages
(8 months) in mice treated with a single high drug dose.
Initially, the resistant parasites produced a low parasitaemia
level and low mortality rate in infected mice. Thereafter, the
parasitaemia level and mortality rate increased to the same
value obtained for mice infected with the wild-type strain.
Long-term treatment with
benznidazole (100 mg/kg/day) cured 71–80% of
mice infected with the wild-type strain. No cure was observed
in mice infected 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 parasitaemia level
was observed in mice infected with the selected parasites.
Benznidazole-resistant parasites showed cross-resistance to
different drugs. Contrary to wild type, all clones analysed
from the resistant T. cruzi population were resistant
to benznidazole. Without drug pressure the resistance phenotype of
clones was far more stable than that presented by the
resistant population. This work demonstrates, for the first time,
the in vivo selection of a population and clones of
T. cruzi resistant to benznidazole, and makes available
an experimental model for the study of mechanisms of drug
resistance in T. cruzi.
Trypanosoma cruzi: cell charge distribution