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

Autor:	Martin J. McPhillie, Michael L. Kent, Hong M. Moulton, Ying Zhou, Mark Hickman, James Gordon, Tatiana Santos, Dyann F. Wirth, Kamal El Bissati, Laura Fraczek, Patty J. Lee, Michael J. Capper, Brigitte Meunieur, Shiv K. Verma, Amanda K. Lukens, Fatima Alibana-Clouser, Christopher R. Weber, Kelsey Wheeler, Joseph Lykins, Rima McLeod, Sarah Dovgin, Leroy Hood, David Donkin, Louis M. Weiss, Taek Kyun Kim, Kai Wang, Colin W. G. Fishwick, Jitender P. Dubey, Hernan Lorenzi, Eric Kim, Stephen P. Muench, Farida Esaa, Yuqing He, Stuart Woods, Gaël Brasseur, Craig W. Roberts, Svetlana V. Antonyuk, Justin L. Sanders, S. Samar Hasnain
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	medicine.medical_specialty Plasmodium falciparum Drug Resistance lcsh:Medicine Quinolones Feces Drug Discovery medicine Animals Humans Intensive care medicine Author Correction lcsh:Science Parasite Egg Count Multidisciplinary business.industry Chronic persistent lcsh:R Oocysts Cytochromes b Disease Models Animal Cats lcsh:Q business Toxoplasma Toxoplasmosis
Zdroj:	Scientific Reports, Vol 10, Iss 1, Pp 1-2 (2020) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
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