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

Identifieur interne : 000006 ( France/Analysis ); précédent : 000005; suivant : 000007

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

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

Source :

RBID : PMC:4944145

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.


Url:
DOI: 10.1038/srep29179
PubMed: 27412848
PubMed Central: 4944145


Affiliations:


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PMC:4944145

Le document en format XML

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<name sortKey="Zhou, Ying" sort="Zhou, Ying" uniqKey="Zhou Y" first="Ying" last="Zhou">Ying Zhou</name>
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<name sortKey="El Bissati, Kamal" sort="El Bissati, Kamal" uniqKey="El Bissati K" first="Kamal" last="El Bissati">Kamal El Bissati</name>
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<name sortKey="Hickman, Mark" sort="Hickman, Mark" uniqKey="Hickman M" first="Mark" last="Hickman">Mark Hickman</name>
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<name sortKey="Muench, Stephen" sort="Muench, Stephen" uniqKey="Muench S" first="Stephen" last="Muench">Stephen Muench</name>
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<name sortKey="Verma, Shiv Kumar" sort="Verma, Shiv Kumar" uniqKey="Verma S" first="Shiv Kumar" last="Verma">Shiv Kumar Verma</name>
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<name sortKey="Weber, Christopher R" sort="Weber, Christopher R" uniqKey="Weber C" first="Christopher R." last="Weber">Christopher R. Weber</name>
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<name sortKey="Moulton, Hong" sort="Moulton, Hong" uniqKey="Moulton H" first="Hong" last="Moulton">Hong Moulton</name>
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<name sortKey="Wang, Kai" sort="Wang, Kai" uniqKey="Wang K" first="Kai" last="Wang">Kai Wang</name>
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<name sortKey="Kim, Taek Kyun" sort="Kim, Taek Kyun" uniqKey="Kim T" first="Taek-Kyun" last="Kim">Taek-Kyun Kim</name>
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<name sortKey="He, Yuqing" sort="He, Yuqing" uniqKey="He Y" first="Yuqing" last="He">Yuqing He</name>
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<institution>Institute for Systems Biology</institution>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Santos, Tatiana" sort="Santos, Tatiana" uniqKey="Santos T" first="Tatiana" last="Santos">Tatiana Santos</name>
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<nlm:aff id="a11">
<institution>Albert Einstein College of Medicine</institution>
, Bronx, New York,
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Woods, Stuart" sort="Woods, Stuart" uniqKey="Woods S" first="Stuart" last="Woods">Stuart Woods</name>
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<nlm:aff id="a12">
<institution>Strathclyde University</institution>
, Glasgow, Scotland,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<name sortKey="Lee, Patty" sort="Lee, Patty" uniqKey="Lee P" first="Patty" last="Lee">Patty Lee</name>
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<name sortKey="Donkin, David" sort="Donkin, David" uniqKey="Donkin D" first="David" last="Donkin">David Donkin</name>
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<author>
<name sortKey="Kim, Eric" sort="Kim, Eric" uniqKey="Kim E" first="Eric" last="Kim">Eric Kim</name>
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<author>
<name sortKey="Fraczek, Laura" sort="Fraczek, Laura" uniqKey="Fraczek L" first="Laura" last="Fraczek">Laura Fraczek</name>
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<country>USA</country>
</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Lykins, Joseph" sort="Lykins, Joseph" uniqKey="Lykins J" first="Joseph" last="Lykins">Joseph Lykins</name>
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<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Esaa, Farida" sort="Esaa, Farida" uniqKey="Esaa F" first="Farida" last="Esaa">Farida Esaa</name>
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<institution>University of Chicago</institution>
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<country>USA</country>
</nlm:aff>
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<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Alibana Clouser, Fatima" sort="Alibana Clouser, Fatima" uniqKey="Alibana Clouser F" first="Fatima" last="Alibana-Clouser">Fatima Alibana-Clouser</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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</author>
<author>
<name sortKey="Dovgin, Sarah" sort="Dovgin, Sarah" uniqKey="Dovgin S" first="Sarah" last="Dovgin">Sarah Dovgin</name>
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<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<author>
<name sortKey="Weiss, Louis" sort="Weiss, Louis" uniqKey="Weiss L" first="Louis" last="Weiss">Louis Weiss</name>
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<nlm:aff id="a11">
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, Bronx, New York,
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Brasseur, Gael" sort="Brasseur, Gael" uniqKey="Brasseur G" first="Gael" last="Brasseur">Gael Brasseur</name>
<affiliation wicri:level="1">
<nlm:aff id="a13">
<institution>CNRS</institution>
, Marseilles,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
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<author>
<name sortKey="Wirth, Dyann" sort="Wirth, Dyann" uniqKey="Wirth D" first="Dyann" last="Wirth">Dyann Wirth</name>
<affiliation wicri:level="1">
<nlm:aff id="a6">
<institution>Harvard School of Public Health</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a7">
<institution>The Broad Institute</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kent, Michael" sort="Kent, Michael" uniqKey="Kent M" first="Michael" last="Kent">Michael Kent</name>
<affiliation wicri:level="1">
<nlm:aff id="a9">
<institution>Oregon State University</institution>
, Corvallis, Oregon,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hood, Leroy" sort="Hood, Leroy" uniqKey="Hood L" first="Leroy" last="Hood">Leroy Hood</name>
<affiliation wicri:level="1">
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</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Meunieur, Brigitte" sort="Meunieur, Brigitte" uniqKey="Meunieur B" first="Brigitte" last="Meunieur">Brigitte Meunieur</name>
<affiliation wicri:level="1">
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<institution>Institute for Integrative Biology of the Cell (12BC)</institution>
, Gif-sur-Yvette,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Roberts, Craig W" sort="Roberts, Craig W" uniqKey="Roberts C" first="Craig W." last="Roberts">Craig W. Roberts</name>
<affiliation wicri:level="1">
<nlm:aff id="a12">
<institution>Strathclyde University</institution>
, Glasgow, Scotland,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hasnain, S Samar" sort="Hasnain, S Samar" uniqKey="Hasnain S" first="S. Samar" last="Hasnain">S. Samar Hasnain</name>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>University of Liverpool</institution>
, Liverpool,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Antonyuk, Svetlana V" sort="Antonyuk, Svetlana V" uniqKey="Antonyuk S" first="Svetlana V." last="Antonyuk">Svetlana V. Antonyuk</name>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>University of Liverpool</institution>
, Liverpool,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fishwick, Colin" sort="Fishwick, Colin" uniqKey="Fishwick C" first="Colin" last="Fishwick">Colin Fishwick</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>University of Leeds</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcleod, Rima" sort="Mcleod, Rima" uniqKey="Mcleod R" first="Rima" last="Mcleod">Rima Mcleod</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
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<idno type="RBID">PMC:4944145</idno>
<idno type="doi">10.1038/srep29179</idno>
<date when="2016">2016</date>
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<idno type="wicri:Area/Main/Exploration">000031</idno>
<idno type="wicri:Area/France/Extraction">000006</idno>
</publicationStmt>
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<biblStruct>
<analytic>
<title xml:lang="en" level="a" type="main">New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections</title>
<author>
<name sortKey="Mcphillie, Martin" sort="Mcphillie, Martin" uniqKey="Mcphillie M" first="Martin" last="Mcphillie">Martin Mcphillie</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>University of Leeds</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Zhou, Ying" sort="Zhou, Ying" uniqKey="Zhou Y" first="Ying" last="Zhou">Ying Zhou</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="El Bissati, Kamal" sort="El Bissati, Kamal" uniqKey="El Bissati K" first="Kamal" last="El Bissati">Kamal El Bissati</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dubey, Jitender" sort="Dubey, Jitender" uniqKey="Dubey J" first="Jitender" last="Dubey">Jitender Dubey</name>
<affiliation wicri:level="1">
<nlm:aff id="a3">
<institution>USDA, Beltsville</institution>
, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lorenzi, Hernan" sort="Lorenzi, Hernan" uniqKey="Lorenzi H" first="Hernan" last="Lorenzi">Hernan Lorenzi</name>
<affiliation wicri:level="1">
<nlm:aff id="a4">
<institution>J Craig Venter Institute</institution>
, Rockville Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Capper, Michael" sort="Capper, Michael" uniqKey="Capper M" first="Michael" last="Capper">Michael Capper</name>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>University of Liverpool</institution>
, Liverpool,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lukens, Amanda K" sort="Lukens, Amanda K" uniqKey="Lukens A" first="Amanda K" last="Lukens">Amanda K. Lukens</name>
<affiliation wicri:level="1">
<nlm:aff id="a6">
<institution>Harvard School of Public Health</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a7">
<institution>The Broad Institute</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hickman, Mark" sort="Hickman, Mark" uniqKey="Hickman M" first="Mark" last="Hickman">Mark Hickman</name>
<affiliation wicri:level="1">
<nlm:aff id="a8">
<institution>Walter Reed Army Institute of Research</institution>
, Silver Spring, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Muench, Stephen" sort="Muench, Stephen" uniqKey="Muench S" first="Stephen" last="Muench">Stephen Muench</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>University of Leeds</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Verma, Shiv Kumar" sort="Verma, Shiv Kumar" uniqKey="Verma S" first="Shiv Kumar" last="Verma">Shiv Kumar Verma</name>
<affiliation wicri:level="1">
<nlm:aff id="a3">
<institution>USDA, Beltsville</institution>
, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Weber, Christopher R" sort="Weber, Christopher R" uniqKey="Weber C" first="Christopher R." last="Weber">Christopher R. Weber</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wheeler, Kelsey" sort="Wheeler, Kelsey" uniqKey="Wheeler K" first="Kelsey" last="Wheeler">Kelsey Wheeler</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Gordon, James" sort="Gordon, James" uniqKey="Gordon J" first="James" last="Gordon">James Gordon</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>University of Leeds</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Sanders, Justin" sort="Sanders, Justin" uniqKey="Sanders J" first="Justin" last="Sanders">Justin Sanders</name>
<affiliation wicri:level="1">
<nlm:aff id="a9">
<institution>Oregon State University</institution>
, Corvallis, Oregon,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Moulton, Hong" sort="Moulton, Hong" uniqKey="Moulton H" first="Hong" last="Moulton">Hong Moulton</name>
<affiliation wicri:level="1">
<nlm:aff id="a9">
<institution>Oregon State University</institution>
, Corvallis, Oregon,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wang, Kai" sort="Wang, Kai" uniqKey="Wang K" first="Kai" last="Wang">Kai Wang</name>
<affiliation wicri:level="1">
<nlm:aff id="a10">
<institution>Institute for Systems Biology</institution>
, Seattle, Washington,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kim, Taek Kyun" sort="Kim, Taek Kyun" uniqKey="Kim T" first="Taek-Kyun" last="Kim">Taek-Kyun Kim</name>
<affiliation wicri:level="1">
<nlm:aff id="a10">
<institution>Institute for Systems Biology</institution>
, Seattle, Washington,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="He, Yuqing" sort="He, Yuqing" uniqKey="He Y" first="Yuqing" last="He">Yuqing He</name>
<affiliation wicri:level="1">
<nlm:aff id="a10">
<institution>Institute for Systems Biology</institution>
, Seattle, Washington,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Santos, Tatiana" sort="Santos, Tatiana" uniqKey="Santos T" first="Tatiana" last="Santos">Tatiana Santos</name>
<affiliation wicri:level="1">
<nlm:aff id="a11">
<institution>Albert Einstein College of Medicine</institution>
, Bronx, New York,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Woods, Stuart" sort="Woods, Stuart" uniqKey="Woods S" first="Stuart" last="Woods">Stuart Woods</name>
<affiliation wicri:level="1">
<nlm:aff id="a12">
<institution>Strathclyde University</institution>
, Glasgow, Scotland,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lee, Patty" sort="Lee, Patty" uniqKey="Lee P" first="Patty" last="Lee">Patty Lee</name>
<affiliation wicri:level="1">
<nlm:aff id="a8">
<institution>Walter Reed Army Institute of Research</institution>
, Silver Spring, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Donkin, David" sort="Donkin, David" uniqKey="Donkin D" first="David" last="Donkin">David Donkin</name>
<affiliation wicri:level="1">
<nlm:aff id="a8">
<institution>Walter Reed Army Institute of Research</institution>
, Silver Spring, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kim, Eric" sort="Kim, Eric" uniqKey="Kim E" first="Eric" last="Kim">Eric Kim</name>
<affiliation wicri:level="1">
<nlm:aff id="a8">
<institution>Walter Reed Army Institute of Research</institution>
, Silver Spring, Maryland,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fraczek, Laura" sort="Fraczek, Laura" uniqKey="Fraczek L" first="Laura" last="Fraczek">Laura Fraczek</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Lykins, Joseph" sort="Lykins, Joseph" uniqKey="Lykins J" first="Joseph" last="Lykins">Joseph Lykins</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Esaa, Farida" sort="Esaa, Farida" uniqKey="Esaa F" first="Farida" last="Esaa">Farida Esaa</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Alibana Clouser, Fatima" sort="Alibana Clouser, Fatima" uniqKey="Alibana Clouser F" first="Fatima" last="Alibana-Clouser">Fatima Alibana-Clouser</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Dovgin, Sarah" sort="Dovgin, Sarah" uniqKey="Dovgin S" first="Sarah" last="Dovgin">Sarah Dovgin</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Weiss, Louis" sort="Weiss, Louis" uniqKey="Weiss L" first="Louis" last="Weiss">Louis Weiss</name>
<affiliation wicri:level="1">
<nlm:aff id="a11">
<institution>Albert Einstein College of Medicine</institution>
, Bronx, New York,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Brasseur, Gael" sort="Brasseur, Gael" uniqKey="Brasseur G" first="Gael" last="Brasseur">Gael Brasseur</name>
<affiliation wicri:level="1">
<nlm:aff id="a13">
<institution>CNRS</institution>
, Marseilles,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Wirth, Dyann" sort="Wirth, Dyann" uniqKey="Wirth D" first="Dyann" last="Wirth">Dyann Wirth</name>
<affiliation wicri:level="1">
<nlm:aff id="a6">
<institution>Harvard School of Public Health</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<nlm:aff id="a7">
<institution>The Broad Institute</institution>
, Boston, Massachusetts,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Kent, Michael" sort="Kent, Michael" uniqKey="Kent M" first="Michael" last="Kent">Michael Kent</name>
<affiliation wicri:level="1">
<nlm:aff id="a9">
<institution>Oregon State University</institution>
, Corvallis, Oregon,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hood, Leroy" sort="Hood, Leroy" uniqKey="Hood L" first="Leroy" last="Hood">Leroy Hood</name>
<affiliation wicri:level="1">
<nlm:aff id="a10">
<institution>Institute for Systems Biology</institution>
, Seattle, Washington,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Meunieur, Brigitte" sort="Meunieur, Brigitte" uniqKey="Meunieur B" first="Brigitte" last="Meunieur">Brigitte Meunieur</name>
<affiliation wicri:level="1">
<nlm:aff id="a14">
<institution>Institute for Integrative Biology of the Cell (12BC)</institution>
, Gif-sur-Yvette,
<country>France</country>
</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Roberts, Craig W" sort="Roberts, Craig W" uniqKey="Roberts C" first="Craig W." last="Roberts">Craig W. Roberts</name>
<affiliation wicri:level="1">
<nlm:aff id="a12">
<institution>Strathclyde University</institution>
, Glasgow, Scotland,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Hasnain, S Samar" sort="Hasnain, S Samar" uniqKey="Hasnain S" first="S. Samar" last="Hasnain">S. Samar Hasnain</name>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>University of Liverpool</institution>
, Liverpool,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Antonyuk, Svetlana V" sort="Antonyuk, Svetlana V" uniqKey="Antonyuk S" first="Svetlana V." last="Antonyuk">Svetlana V. Antonyuk</name>
<affiliation wicri:level="1">
<nlm:aff id="a5">
<institution>University of Liverpool</institution>
, Liverpool,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Fishwick, Colin" sort="Fishwick, Colin" uniqKey="Fishwick C" first="Colin" last="Fishwick">Colin Fishwick</name>
<affiliation wicri:level="1">
<nlm:aff id="a1">
<institution>University of Leeds</institution>
, Leeds,
<country>UK</country>
</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
<author>
<name sortKey="Mcleod, Rima" sort="Mcleod, Rima" uniqKey="Mcleod R" first="Rima" last="Mcleod">Rima Mcleod</name>
<affiliation wicri:level="1">
<nlm:aff id="a2">
<institution>University of Chicago</institution>
, Chicago,
<country>USA</country>
</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Scientific Reports</title>
<idno type="eISSN">2045-2322</idno>
<imprint>
<date when="2016">2016</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">
<p>
<italic>Toxoplasma gondii</italic>
, 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
<italic>T. gondii</italic>
forms cysts
<italic>in vitro</italic>
that induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express
<italic>cytochrome b</italic>
. Using these models, we envisioned, and then created, novel 4-(1
<italic>H</italic>
)-quinolone scaffolds that target the cytochrome
<italic>bc</italic>
<sub>
<italic>1</italic>
</sub>
complex Q
<sub>i</sub>
site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC
<sub>50</sub>
, 30 nM) and cysts (IC
<sub>50</sub>
, 4 μM)
<italic>in vitro,</italic>
and
<italic>in vivo</italic>
(25 mg/kg), and drug resistant
<italic>Plasmodium falciparum</italic>
(IC
<sub>50</sub>
, <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the
<italic>bc</italic>
<sub>
<italic>1</italic>
</sub>
complex Q
<sub>i</sub>
site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.</p>
</div>
</front>
<back>
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