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

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

in 13/106 / 13/51 / 45 / 45/23 / 45/91 / 631/154 / 631/535 / 631/553 / 64 / 692/308 / 692/420 / Animals / Bacteriology / Biochemistry, Molecular Biology / Bradyzoites / Cats / Chemical Sciences / Chronic infection / Cysts / Cytochrome / Cytochrome b / Cytochrome bc1 / Cytochromes b - genetics / Disease Models, Animal / Drug development / Drug Discovery / Drug resistance / Drug Resistance - genetics / Feces - parasitology / Genomes / Human health and pathology / Humanities and Social Sciences / Humans / Infections / Infectious diseases / Life Sciences / Malaria / Medicinal Chemistry / Microbiology and Parasitology / multidisciplinary / Mutants / Mutation / Oocysts / Oocysts - drug effects / Oocysts - pathogenicity / Parasite Egg Count / Parasites / Plasmodium falciparum / Plasmodium falciparum - drug effects / Plasmodium falciparum - pathogenicity / Protozoa / Quinolones - pharmacology / Science / Structural Biology / Toxoplasma - drug effects / Toxoplasma - genetics / Toxoplasma - pathogenicity / Toxoplasmosis / Toxoplasmosis - drug therapy / Toxoplasmosis - genetics / Toxoplasmosis - parasitology / Vector-borne diseases / Yeast / Yeasts

2016

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

2016

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

2016

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Journal Article

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

Lykins, Joseph,

Antonyuk, Svetlana V.,

Weiss, Louis,

Donkin, David,

Hasnain, S. Samar,

Dubey, Jitender,

Wheeler, Kelsey,

Fishwick, Colin,

Lee, Patty,

Fraczek, Laura,

Weber, Christopher R.,

Moulton, Hong,

Sanders, Justin,

Woods, Stuart,

Kim, Taek-Kyun,

Alibana-Clouser, Fatima,

Roberts, Craig W.,

Dovgin, Sarah,

Brasseur, Gael,

Capper, Michael,

Kim, Eric,

McPhillie, Martin,

Hood, Leroy,

Wirth, Dyann,

Hickman, Mark,

Santos, Tatiana,

Esaa, Farida,

Zhou, Ying,

Kent, Michael,

Verma, Shiv Kumar,

Lorenzi, Hernan,

Lukens, Amanda K,

Muench, Stephen,

Gordon, James,

He, Yuqing,

El Bissati, Kamal,

Wang, Kai,

Meunieur, Brigitte,

McLeod, Rima

2016

Overview

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-(1 H )-quinolone scaffolds that target the cytochrome bc 1 complex Q i site, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC 50 , 30 nM) and cysts (IC 50 , 4 μM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC 50 , <30 nM), with clinically relevant synergy. Mutant yeast and co-crystallographic studies demonstrate binding to the bc 1 complex Q i site. Our results have direct impact on improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.

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Publisher

Nature Publishing Group UK,Nature Publishing Group

Subject

13/106

/ 13/51

/ 45

/ 45/23

/ 45/91

/ 631/154

/ 631/535