Fig. 3: AN15368 cures T. cruzi infection in mice.
a, Fluorescence intensity of C57BL/6J mice infected in the footpads with 2.5 × 105 tdTomato-expressing T. cruzi was measured by in vivo imaging directly before (2 dpi) and 2 d after (4 dpi) a single oral dose of the compounds (50 mg kg−1). The parasite proliferation index after treatment was calculated as described in Methods (n = 10 individual feet). b, A daily oral treatment of the indicated compounds (10 mg kg−1) was administered for 40 d to C57BL/6J mice acutely infected with T. cruzi beginning at 17 dpi. Mice were immunosuppressed at the end of the treatment and samples were collected for parasitemia, haemoculture and qPCR of skeletal muscle (untreated, AN14817 and AN15129: n = 8; AN15368 and AN14353: n = 7; naive: n = 3 mice). c, Acutely infected mice (20 dpi) were treated orally with 10 mg kg−1 of compounds for 20 d. Parasite load in skeletal muscle was quantified by qPCR following immunosuppression at the end of the treatment. Dotted line represents the cut-off for the qPCR assay (untreated, AN16109, AN15368 and AN14353: n = 6; AN14817: n = 5; naive: n = 3 mice). d, On days 13–33 post infection, oral doses of AN15368 were administered at the indicated concentrations to hairless mice infected i.p. with 5 × 104 luciferase-expressing T. cruzi. Bioluminiscence signals from whole mouse ventral images were acquired and quantified throughout the treatment by in vivo imaging (untreated, 7 mice; treated, 5 mice). Dashed line indicates background level in uninfected mice. e, C57BL/6J mice infected with 104 T. cruzi i.p. were treated daily for 40 d, starting at 15 dpi with AN16109 or AN15368 (both at 2.5 mg kg−1). Parasite load was determined by qPCR of skeletal muscle samples after immunosuppression and blood samples were analysed by light microscopy and haemoculture (AN16109: n = 8; AN15368: n = 7; naive: n = 3; untreated: n = 2 mice). Red symbols denote animals in which parasites were detected by microscopy and/or haemoculture. Data are presented as mean ± s.e.m. Asterisks represent the statistical significance of the difference between each treated group and the untreated control. For a, b and c: Mann-Whitney test, two tailed; for e: unpaired t-test, 95% confidence interval. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.
