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

McPhillie, Martin and Zhou, Ying and El Bissati, Kamal and Dubey, Jitender and Lorenzi, Hernan and Capper, Michael and Lukens, Amanda K and Hickman, Mark and Muench, Stephen and Verma, Shiv Kumar and Weber, Christopher R. and Wheeler, Kelsey and Gordon, James and Sanders, Justin and Moulton, Hong and Wang, Kai and Kim, Taek-Kyun and He, Yuqing and Santos, Tatiana and Woods, Stuart and Lee, Patty and Donkin, David and Kim, Eric and Fraczek, Laura and Lykins, Joseph and Esaa, Farida and Alibana-Clouser, Fatima and Dovgin, Sarah and Weiss, Louis and Brasseur, Gael and Wirth, Dyann and Kent, Michael and Hood, Leroy and Meunieur, Brigitte and Roberts, Craig W. and Hasnain, S. Samar and Antonyuk, Svetlana V. and Fishwick, Colin and McLeod, Rima (2016) New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Scientific Reports, 6. pp. 1-23. 29179. ISSN 2045-2322

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    Abstract

    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 Qi site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.