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

Martin McPhillie, Ying Zhou, Kamal El Bissati, Jitender Dubey, Hernan Lorenzi, Michael Capper, Amanda K. Lukens, Mark Hickman, Stephen Muench, Shiv Kumar Verma, Christopher R. Weber, Kelsey Wheeler, James Gordon, Justin Sanders, Hong Moulton, Kai Wang, Taek Kyun Kim, Yuqing He, Tatiana Santos, Stuart WoodsPatty Lee, David Donkin, Eric Kim, Laura Fraczek, Joseph Lykins, Farida Esaa, Fatima Alibana-Clouser, Sarah Dovgin, Louis Weiss, Gael Brasseur, Dyann Wirth, Michael Kent, Leroy Hood, Brigitte Meunieur, Craig W. Roberts, S. Samar Hasnain, Svetlana V. Antonyuk, Colin Fishwick, Rima McLeod

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Article number29179
JournalScientific reports
Volume6
DOIs
StatePublished - Jul 14 2016

ASJC Scopus subject areas

  • General

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    McPhillie, M., Zhou, Y., El Bissati, K., Dubey, J., Lorenzi, H., Capper, M., Lukens, A. K., Hickman, M., Muench, S., Verma, S. K., Weber, C. R., Wheeler, K., Gordon, J., Sanders, J., Moulton, H., Wang, K., Kim, T. K., He, Y., Santos, T., ... McLeod, R. (2016). New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Scientific reports, 6, [29179]. https://doi.org/10.1038/srep29179