TY - JOUR
T1 - New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections
AU - McPhillie, Martin
AU - Zhou, Ying
AU - El Bissati, Kamal
AU - Dubey, Jitender
AU - Lorenzi, Hernan
AU - Capper, Michael
AU - Lukens, Amanda K.
AU - Hickman, Mark
AU - Muench, Stephen
AU - Verma, Shiv Kumar
AU - Weber, Christopher R.
AU - Wheeler, Kelsey
AU - Gordon, James
AU - Sanders, Justin
AU - Moulton, Hong
AU - Wang, Kai
AU - Kim, Taek Kyun
AU - He, Yuqing
AU - Santos, Tatiana
AU - Woods, Stuart
AU - Lee, Patty
AU - Donkin, David
AU - Kim, Eric
AU - Fraczek, Laura
AU - Lykins, Joseph
AU - Esaa, Farida
AU - Alibana-Clouser, Fatima
AU - Dovgin, Sarah
AU - Weiss, Louis
AU - Brasseur, Gael
AU - Wirth, Dyann
AU - Kent, Michael
AU - Hood, Leroy
AU - Meunieur, Brigitte
AU - Roberts, Craig W.
AU - Hasnain, S. Samar
AU - Antonyuk, Svetlana V.
AU - Fishwick, Colin
AU - McLeod, Rima
N1 - Funding Information:
This work was supported by Grant number AI U01AI082180 from NIH NIAID DMID and by the Mann Cornwell Family, the Engel family and "Taking out Toxo", the Rooney and the Morel families. University of Liverpool team was supported via Wellcome Trust and BBSRC and would like to acknowledge on-going collaboration with Professor Paul O'Neil (Chemistry, U of Liverpool) and Prof Giancarlo Biangini (LSTM) on a related project on Plasmodium falciparum. We acknowledge the support of crystallographic facilities at DIAMOND (UK). Research reported in this publication also was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Contract Number HHSN272200900007C and Award Number U19AI110819. The team at the Institute for Systems Biology is partially supported by research contracts from DTRA and DOD (HDTRA1-13-C-0055, W911NF-09-D0001 and W911SR-07-C0101). We acknowledge Openeye Inc for the generous provision of an Academic software license. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Ian Begeman for his assistance in the preparation of this manuscript. We thank Eleonor Lago MD PhD for providing the cost analysis data for Brazil.
PY - 2016/7/14
Y1 - 2016/7/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978473062&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978473062&partnerID=8YFLogxK
U2 - 10.1038/srep29179
DO - 10.1038/srep29179
M3 - Article
C2 - 27412848
AN - SCOPUS:84978473062
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 29179
ER -
