New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections
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Author
McPhillie, Martin
Zhou, Ying
El Bissati, Kamal
Dubey, Jitender
Lorenzi, Hernan
Capper, Michael
Hickman, Mark
Muench, Stephen
Verma, Shiv Kumar
Weber, Christopher R.
Wheeler, Kelsey
Gordon, James
Sanders, Justin
Moulton, Hong
Wang, Kai
Kim, Taek-Kyun
He, Yuqing
Santos, Tatiana
Woods, Stuart
Lee, Patty
Donkin, David
Kim, Eric
Fraczek, Laura
Lykins, Joseph
Esaa, Farida
Alibana-Clouser, Fatima
Dovgin, Sarah
Weiss, Louis
Brasseur, Gael
Kent, Michael
Hood, Leroy
Meunieur, Brigitte
Roberts, Craig W.
Hasnain, S. Samar
Antonyuk, Svetlana V.
Fishwick, Colin
McLeod, Rima
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1038/srep29179Metadata
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McPhillie, M., Y. Zhou, K. El Bissati, J. Dubey, H. Lorenzi, M. Capper, A. K. Lukens, et al. 2016. “New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.” Scientific Reports 6 (1): 29179. doi:10.1038/srep29179. http://dx.doi.org/10.1038/srep29179.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944145/pdf/Terms of Use
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