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

Martin McPhillie, Ying Zhou, Kamal El Bissati, Jitender Dubey, Hernan Lorenzi, Michael Capper, Amanda K Lukens, Mark Hickman, Stephen Muench, Shiv Kumar Verma, Christopher R. Weber, Kelsey Wheeler, James Gordon, Justin Sanders, Hong Moulton, Kai Wang, Taek-Kyun Kim, Yuqing He, Tatiana Santos, Stuart Woods & 19 others Patty Lee, David Donkin, Eric Kim, Laura Fraczek, Joseph Lykins, Farida Esaa, Fatima Alibana-Clouser, Sarah Dovgin, Louis Weiss, Gael Brasseur, Dyann Wirth, Michael Kent, Leroy Hood, Brigitte Meunieur, Craig W. Roberts, S. Samar Hasnain, Svetlana V. Antonyuk, Colin Fishwick, Rima McLeod

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.
LanguageEnglish
Article number29179
Pages1-23
Number of pages23
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 14 Jul 2016

Fingerprint

Cysts
Inhibitory Concentration 50
Qi
Toxoplasma
Infection
4-Quinolones
Parasitic Diseases
Cytochromes b
Oocysts
Electron Transport Complex III
Toxoplasmosis
Plasmodium falciparum
Pharmaceutical Preparations
Malaria
Cats
Yeasts
Brain
In Vitro Techniques

Keywords

  • apicomplexan infections
  • toxoplasma gondii
  • parasitic infection

Cite this

McPhillie, M., Zhou, Y., El Bissati, K., Dubey, J., Lorenzi, H., Capper, M., ... McLeod, R. (2016). New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Scientific Reports, 6, 1-23. [29179]. https://doi.org/10.1038/srep29179
McPhillie, Martin ; Zhou, Ying ; El Bissati, Kamal ; Dubey, Jitender ; Lorenzi, Hernan ; Capper, Michael ; Lukens, Amanda K ; Hickman, Mark ; Muench, Stephen ; Verma, Shiv Kumar ; Weber, Christopher R. ; Wheeler, Kelsey ; Gordon, James ; Sanders, Justin ; Moulton, Hong ; Wang, Kai ; Kim, Taek-Kyun ; He, Yuqing ; Santos, Tatiana ; Woods, Stuart ; Lee, Patty ; Donkin, David ; Kim, Eric ; Fraczek, Laura ; Lykins, Joseph ; Esaa, Farida ; Alibana-Clouser, Fatima ; Dovgin, Sarah ; Weiss, Louis ; Brasseur, Gael ; Wirth, Dyann ; Kent, Michael ; Hood, Leroy ; Meunieur, Brigitte ; Roberts, Craig W. ; Hasnain, S. Samar ; Antonyuk, Svetlana V. ; Fishwick, Colin ; McLeod, Rima. / New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. In: Scientific Reports. 2016 ; Vol. 6. pp. 1-23.
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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.",
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McPhillie, M, Zhou, Y, El Bissati, K, Dubey, J, Lorenzi, H, Capper, M, Lukens, AK, Hickman, M, Muench, S, Verma, SK, Weber, CR, Wheeler, K, Gordon, J, Sanders, J, Moulton, H, Wang, K, Kim, T-K, He, Y, Santos, T, Woods, S, Lee, P, Donkin, D, Kim, E, Fraczek, L, Lykins, J, Esaa, F, Alibana-Clouser, F, Dovgin, S, Weiss, L, Brasseur, G, Wirth, D, Kent, M, Hood, L, Meunieur, B, Roberts, CW, Hasnain, SS, Antonyuk, SV, Fishwick, C & McLeod, R 2016, 'New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections' Scientific Reports, vol. 6, 29179, pp. 1-23. https://doi.org/10.1038/srep29179

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

In: Scientific Reports, Vol. 6, 29179, 14.07.2016, p. 1-23.

Research output: Contribution to journalArticle

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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

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.

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