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

DOI: 10.1038/srep29179 DOI Help

Authors: Martin Mcphillie (University of Leeds) , Ying Zhou (University of Chicago) , Kamal El Bissati (University of Chicago) , Jitender Dubey (USDA) , Hernan Lorenzi (J Craig Venter Institute) , Michael Capper (University of Liverpool) , Amanda K. Lukens (Harvard School of Public Health; The Broad Institute) , Mark Hickman (Walter Reed Army Institute of Research) , Stephen Muench (University of Leeds) , Shiv Kumar Verma (USDA) , Christopher R. Weber (University of Chicago) , Kelsey Wheeler (University of Chicago) , James Gordon (University of Leeds) , Justin Sanders (Oregon State University) , Hong Moulton (Oregon State University) , Kai Wang (Institute for Systems Biology) , Taek-kyun Kim (Institute for Systems Biology) , Yuqing He (Institute for Systems Biology) , Tatiana Santos (Albert Einstein College of Medicine) , Stuart Woods (Strathclyde University) , Patty Lee (Walter Reed Army Institute of Research) , David Donkin (Walter Reed Army Institute of Research) , Eric Kim (Walter Reed Army Institute of Research) , Laura Fraczek (University of Chicago) , Joseph Lykins (University of Chicago) , Farida Esaa (University of Chicago) , Fatima Alibana-clouser (University of Chicago) , Sarah Dovgin (University of Chicago) , Louis Weiss (Albert Einstein College of Medicine) , Gael Brasseur (CNRS) , Dyann Wirth (Harvard School of Public Health; The Broad Institute) , Michael Kent (Oregon State University) , Leroy Hood (Institute for Systems Biology) , Brigitte Meunieur (Institute for Integrative Biology of the Cell (12BC)) , Craig W. Roberts (Strathclyde University) , S. Samar Hasnain (University of Liverpool) , Svetlana V. Antonyuk (University of Liverpool) , Colin Fishwick (University of Leeds) , Rima Mcleod (University of Chicago)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Scientific Reports , VOL 6

State: Published (Approved)
Published: July 2016
Diamond Proposal Number(s): 11740

Open Access Open Access

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.

Journal Keywords: Drug discovery; Medical research; Pathogenesis; Structural biology; Systems biology

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Documents:
srep29179.pdf