title: New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections.
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.
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: McPhillie
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Kamal
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authors.lastname: El Bissati
authors.affiliation: USDA, Beltsville, Maryland, USA.
authors.forename: Jitender
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authors.lastname: Dubey
authors.affiliation: J Craig Venter Institute, Rockville Maryland, USA.
authors.forename: Hernan
authors.initials: H
authors.lastname: Lorenzi
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Capper
authors.affiliation: Harvard School of Public Health, Boston, Massachusetts, USA.|The Broad Institute, Boston, Massachusetts, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Lukens
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Muench
authors.affiliation: USDA, Beltsville, Maryland, USA.
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Verma
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Wheeler
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: James
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Oregon State University, Corvallis, Oregon, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Sanders
authors.affiliation: Oregon State University, Corvallis, Oregon, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Moulton
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Taek-Kyun
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: He
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Santos
authors.affiliation: Strathclyde University, Glasgow, Scotland, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Woods
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Patty
authors.initials: P
authors.lastname: Lee
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Donkin
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Kim
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Fraczek
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lykins
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Farida
authors.initials: F
authors.lastname: Esaa
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Alibana-Clouser
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dovgin
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Weiss
authors.affiliation: CNRS, Marseilles, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Brasseur
authors.affiliation: Harvard School of Public Health, Boston, Massachusetts, USA.|The Broad Institute, Boston, Massachusetts, USA.
authors.forename: Dyann
authors.initials: D
authors.lastname: Wirth
authors.affiliation: Oregon State University, Corvallis, Oregon, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Kent
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.affiliation: Institute for Integrative Biology of the Cell (12BC), Gif-sur-Yvette, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunieur
authors.affiliation: Strathclyde University, Glasgow, Scotland, UK.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Roberts
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: S Samar
authors.initials: SS
authors.lastname: Hasnain
authors.affiliation: University of Liverpool, Liverpool, UK.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Antonyuk
authors.affiliation: University of Leeds, Leeds, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Fishwick
authors.affiliation: University of Chicago, Chicago, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
mesh_terms: D000818:Animals; D002415:Cats; D045303:Cytochromes b / Q000235:genetics; D004195:Disease Models, Animal; D055808:Drug Discovery; D004351:Drug Resistance / Q000235:genetics; D005243:Feces / Q000469:parasitology; D006801:Humans; D033661:Oocysts / Q000187:drug effects / Q000472:pathogenicity; D010270:Parasite Egg Count; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D015363:Quinolones / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000235:genetics / Q000469:parasitology
chemical_list: D015363:Quinolones; D045303:Cytochromes b