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

Author
item MCPHILLIE, MARTIN - Leeds University
item ZHOU, YING - University Of Chicago
item Dubey, Jitender
item LORENZI, HERNAN - J Craig Venter Institute
item CAPPER, MICHAEL - University Of Liverpool
item LUKENS, AMANDA - Harvard School Of Public Health
item HICKMAN, MARK - Walter Reed Army Institute
item MUENCH, STEPHEN - University Of Leeds
item VERMA, SHIV - Orise Fellow
item WEBER, CHRISTOPHER - University Of Chicago
item WHEELER, KELSEY - University Of Chicago
item GORDON, JAMES - University Of Leeds
item SANDERS, JUSTIN - Oregon State University
item MOULTON, HONG - Oregon State University
item WANG, KAI - Institute For Systems Biology
item KIM, TAEK-KYUN - Institute For Systems Biology
item HE, YUQING - Institute For Systems Biology
item SANTOS, TATIANA - Albert Einstein College Of Medicine
item WOODS, STUART - University Of Strathclyde
item LEE, PATTY - Walter Reed Army Institute
item DONKIN, DAVID - Walter Reed Army Institute
item KIM, ERIC - Walter Reed Army Institute
item FRACZEK, LAURA - University Of Chicago
item LYKINS, JOSEPH - University Of Chicago
item ESAA, FARIDA - University Of Chicago
item ALIBANA-CLOUSER, FATIMA - University Of Chicago
item DOVGIN, SARAH - University Of Chicago
item WEISS, LOUIS - Albert Einstein College Of Medicine
item BRASSEUR, GAEL - National Council For Scientific Research-Cnrs
item WIRTH, DYANN - Harvard School Of Public Health
item KENT, MICHAEL - Oregon State University
item HOOD, LEROY - Institute For Systems Biology
item MEUNIEUR, BRIGITTE - Institut De Biologie Integrative De La Cellule
item ROBERTS, CRAIG - University Of Strathclyde
item HASNAIN, S. SAMAR - University Of Liverpool
item ANTONYUK, SVETLANA - University Of Liverpool
item FISHWICK, COLIN - University Of Leeds
item MCLEOD, RIMA - University Of Chicago

Submitted to: Nature Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/31/2016
Publication Date: 7/12/2016
Citation: Mcphillie, M., Zhou, Y., Dubey, J.P., Lorenzi, H., Capper, M., Lukens, A.K., Hickman, M., Muench, S., Verma, S., Weber, C., Wheeler, K., Gordon, J., Sanders, J., Moulton, H., Wang, K., Kim, T., 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, C., Hasnain, S., Antonyuk, S.V., Fishwick, C., Mcleod, R. 2016. New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. Nature Scientific Reports. 6:29179.

Interpretive Summary: Toxoplasmosis continues to be a major health problem worldwide. T.gondii is the second most common single cause of food born associated death in the U.S. This parasite causes devastating disease that damages the brain and eyes of the fetus, eyes of some older children and adults who acquire this infection post-natally, and it causes brain disease and fatalities in those with immune-compromise. It also causes epilepsy. This infection is the most common parasitic infection of the human brain, throughout the world. T.gondii remains in the human brain lifelong for 2 billion people world-wide and currently is untreatable. Parasites can recrudesce any time, and do so especially in those with immune compromise or congenital infection. This parasite also causes recurrent episodes of active eye disease in those with post-natally acquired ocular toxoplasmosis. Available medicines for the rapidly growing life cycle stage are effective but have some limitations due to toxicity and hypersensitivity. Slower growing encysted bradyzoite-like organisms are not treatable with any present medicine. In the present study, authors developed in vitro and in vivo systems to screen drugs against encysted parasites, and successfully used this novel approach to identify novel drugs that show good efficacy. The novel compound also was shown to have activity against drug-resistant strains of malaria, elevating the potential public health benefits to be derived from this breakthrough. These findings will interest physicians, veterinarians, epidemiologists, and the pharmaceutical industry.

Technical Abstract: Toxoplasma gondii, the most common parasitic infection of the human brain and eye, persists across lifetimes, can progressively damage sight, and is currently incurable. New, curative medicines are needed urgently. Herein, we developed novel models to facilitate drug development: EGS strain T. gondii forms cysts in vitro that can induce oocysts in cats, the gold standard criterion for cysts. These cysts highly express cytochrome b. Using these models, we created novel 4-(1H)-quinolones that target the Qi site of cytochrome bc1 complex, of which, a substituted 5,6,7,8-tetrahydroquinolin-4-one inhibits active infection (IC50, 20nM) and cysts (IC50, 2.5 µM) in vitro, and in vivo (25 mg/kg), and drug resistant Plasmodium falciparum (IC50, <30nM), with clinically relevant synergy. Mutant yeast and co-crystallization studies demonstrate binding to the Qi site of bc1 complex. This new scaffold facilitates improving outcomes for those with toxoplasmosis, malaria, and ~2 billion persons chronically infected with encysted bradyzoites.