Background: Two pyridine derivatives were identified as promising drug candidates in animal models of Chagas disease. Results: They were tested as sterol 14␣-demethylase (CYP51) inhibitors, and x-ray co-structures with T. cruzi CYP51 were determined. Conclusion:The structures explain the potency and selectivity of the compound. Significance: Structural information contributes to a better understanding of P450 inhibition and will facilitate rational design of pathogen-specific drugs.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

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The debilitating zoonosis Chagas disease (CD) is caused by infection with the flagellate protozoan Trypanosoma cruzi. One century after its discovery, a curative agent remains elusive. Immune evasion by T. cruzi results in a poorly controlled infection in the host, which can end in either sudden death or a fatal chronic disease that often eventuates after years of an asymptomatic infection. Polyparasitism or mixed/concurrent infections occur more often than not and contribute to the high degree of variability observed across both disease progression and the success of therapeutic interventions. A thorough understanding of the effects of polyparasitism on CD is essential for improving the likelihood of containing, treating, and eventually eliminating CD.

The ‘quenda genotype’ of Giardia was first identified in quenda (syn. southern brown bandicoots, Isoodon obesulus) in Western Australia in 2004. We aimed to formally describe this genotype as a species of Giardia, Giardia peramelis. Seventy five faecal samples positive for G. peramelis were obtained from quenda within the Statistical Division of Perth, Western Australia. These samples were used in morphological and molecular characterisation of G. peramelis. PCR amplification and sequencing was most successful at the 18S rRNA and ITS1-5.8s-ITS2 loci. Phylogenetic analyses placed G. peramelis external to the ‘Giardia duodenalis species complex’ and Giardia microti. This confirmed the uniqueness of G. peramelis, warranting classification as a separate species of Giardia. Study findings suggest quenda are a natural host for G. peramelis.