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ARS Home Northeast Area Beltsville, Maryland (BARC) Beltsville Agricultural Research Center Animal Parasitic Diseases Laboratory Research Publications at this Location





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


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