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Inhibitory Effects of Sinefungin and its Cyclic Analog on the Multiplication of Trypanosoma cruzi Isolates
Abstract
Sinefungin and its cyclic analog were evaluated in vitro for activity against the multiplication of Trypanosoma cruzi. When either drug was tested for eight days on twelve T. cruzi epimastigote isolates, an 800-fold difference in drug sensitivity was found. Both drugs were trypanostatics at a concentration range from 0.1 µg/ml to 300 µg/ml. The 50% effective concentration (EC50) of sinefungin and its cyclic analog at which the growth of a given isolate was inhibited was 0.38 µg/ml for sinefungin and 0.31 µg/ml for the cyclic analog against the Ma, Marin, OPS-86, Y, and Ya isolates, and > 300 µg/ml for sinefungin and 217 µg/ml for the cyclic analog against the A-35, Bertoldo, DS, EP, ES, OPS-58, and FL isolates. Incubation of drug-sensitive isolates for more than 10 days in glucose-saline (GS) medium, but not in minimal essential medium, in the presence of a 30-fold EC50 concentration of the drug induced an increase in the drug-resistant population, which maintained this phenotype for several passages in drug-free culture medium. Growth curves were analyzed as a function of parasite inoculum; it was observed that with sinefunginsensitive T. cruzi epimastigote isolates grown in GS medium in the presence of 10 µg/ml of the drug, the inhibitory effects of the drug were dependent on the initial inoculum: 1 × 103-1 × 104 parasites/ml were strongly inhibited even after 16 days. Significant impairment of thymidine incorporation into the DNA of parasites by both drugs was observed only in drug-sensitive epimastigote isolates. Vero cell-derived trypomastigotes of the twelve T. cruzi isolates studied grew in the presence of 50 µg/ml of sinefungin or the cyclic analog in culture medium, which suggests a stage-specific inhibitory effect.