Two novel calcium-dependent kinase 1-inhibitors interfere with vertical transmission in mice infected with Neospora caninum tachyzoites.

Müller, Joachim; Aguado Martinez, Adriana; Balmer, Vreni; Maly, Dustin J; Fan, Erkang; Ortega-Mora, Luis-Miguel; Ojo, Kayode K; Van Voorhis, Wesley C; Hemphill, Andrew (2017). Two novel calcium-dependent kinase 1-inhibitors interfere with vertical transmission in mice infected with Neospora caninum tachyzoites. Antimicrobial agents and chemotherapy, 61(4) American Society for Microbiology 10.1128/AAC.02324-16

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We present the effects of two novel bumped kinase inhibitors, BKI-1517 and BKI-1553 against Neospora caninum tachyzoites in vitro and in experimentally infected pregnant mice. The compounds inhibited tachyzoite proliferation of a transgenic beta-galactosidase reporter strain cultured in human foreskin fibroblasts with IC50 values of 0.05 ± 0.03 and 0.18 ± 0.03 μM, respectively. As assessed by Alamar blue assay, fibroblast IC50 values were above 20 μM, however, morphological changes occurred in cultures treated with more than 5 μM BKI-1517 after prolonged (>6 days) exposure. Treatment of intracellular tachyzoites with 5 μM BKI-1553 for 6 days inhibited endodyogeny by interfering in the separation of newly formed zoites from a larger multinucleated parasite mass. In contrast, parasites treated with 5 μM BKI-1517 did not form large complexes, and showed much more evidence of cell death. However, after a treatment duration of 10 days in vitro, both compounds failed to completely prevent regrowth of parasites from culture. BALB/c mice experimentally infected with Nc-Spain7, and then treated during 6 days with BKI-1517 or BKI-1553 at different dosages, showed a significant reduction of the cerebral parasite load. Fertility was, however, impaired by BKI-1517 when applied at 50mg/kg/day. At 20mg/kg/day BKI-1517 significantly inhibited vertical transmission of N. caninum to pups and increased survival of offspring. BKI-1553 was less detrimental to fertility and also provided a significant, but clearly less pronounced protection of dams and offspring. These results demonstrate that - when judiciously applied - this compound class protects offspring from vertical transmission and disease.

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