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New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

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  • Toxoplasma gondii, the most common parasitic infection of human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we develop novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we envisioned, and then created, novel 4-(1H)-quinolone scaffolds that target the cytochrome bc₁ complex Qi site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC₅₀, 30 nM) and cysts (IC₅₀, 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC₅₀, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc₁ complex Q[subscript]i site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.
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  • McPhillie, M., Zhou, Y., El Bissatai, K., Dubey, J., Lorenzi, H., Capper, M., ... & McLeod, Rima (2016). New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Scientific Reports, 6, 29179. doi:10.1038/srep29179
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  • This work was supported by Grant number AI U01AI082180 from NIH NIAID DMID and by the Mann Cornwell Family, the Engel family and "Taking out Toxo", the Rooney and the Morel families. University of Liverpool team was supported via Wellcome Trust and BBSRC and would like to acknowledge ongoing collaboration with Professor Paul O'Neil (Chemistry, U of Liverpool) and Prof Giancarlo Biangini (LSTM) on a related project on Plasmodium falciparum. We acknowledge the support of crystallographic facilities at DIAMOND (UK). Research reported in this publication also was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Contract Number HHSN272200900007C and Award Number U19AI110819. The team at the Institute for Systems Biology is partially supported by research contracts from DTRA and DOD (HDTRA1-13-C-0055, W911NF-09-D0001 and W911SR-07-C0101). We acknowledge Openeye Inc for the generous provision of an Academic software license.
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