Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi

Detalhes bibliográficos
Autor(a) principal: Rocha-Hasler, Marianne
Data de Publicação: 2021
Outros Autores: Oliveira, Gabriel Melo de, Gama, Aline Nefertiti da, Fiuza, Ludmila Ferreira de Almeida, Fesser, Anna Frieda, Cal, Monica, Rocchetti, Romina, Peres, Raiza Brandão, Guan, Xue Li, Kaiser, Marcel, Soeiro, Maria de Nazaré Correia, Mässer, Pascal
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/48979
Resumo: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
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spelling Rocha-Hasler, MarianneOliveira, Gabriel Melo deGama, Aline Nefertiti daFiuza, Ludmila Ferreira de AlmeidaFesser, Anna FriedaCal, MonicaRocchetti, RominaPeres, Raiza BrandãoGuan, Xue LiKaiser, MarcelSoeiro, Maria de Nazaré CorreiaMässer, Pascal2021-09-03T19:41:50Z2021-09-03T19:41:50Z2021ROCHA-HASLER, Marianne et al. Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi. Front. Cell. Infect. Microbiol., v. 11, Article 617917, 11 p, Mar. 2021.2235-2988https://www.arca.fiocruz.br/handle/icict/4897910.3389/fcimb.2021.617917engFrontiers MediaDoença de ChagasTrypanosoma cruziCloridrato de tomatidinaInibidor da biossíntese de lipídiosCombinação de drogasChagas DiseaseTomatidine hydrochlorideDrug combinationTrypanosoma cruziLipid biosynthesis inhibitorCombination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruziinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Systems Biology of Lipid Metabolism in Human Health and Diseases Laboratory, Lee Kong Chian School of Medicine. Singapore, Singapore.Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil.Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.Azoles such as posaconazole (Posa) are highly potent against Trypanosoma cruzi. However, when tested in chronic Chagas disease patients, a high rate of relapse after Posa treatment was observed. It appears that inhibition of T. cruzi cytochrome CYP51, the target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable combination partners of azoles, we have selected a set of inhibitors of sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted in vitro against the proliferative forms of T. cruzi, extracellular epimastigotes and intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15 tested compounds presented higher or equal activity as benznidazole (Bz), with EC50 values ≤2.2 mM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The combination of TH with Posa displayed a synergistic profile against amastigotes, with a mean SFICI value of 0.2. In vivo assays using an acute mouse model of T. cruzi infection demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/ kg. As observed in vitro, the best combo proportion in vivo was the ratio 3 TH:1 Posa. The combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These initial results indicate a potential for the combination of posaconazole with tomatidine against T. cruzi.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/48979/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALMArianeHasler_GabrielOliveira_etal_IOC_2021.pdfMArianeHasler_GabrielOliveira_etal_IOC_2021.pdfapplication/pdf1539160https://www.arca.fiocruz.br/bitstream/icict/48979/2/MArianeHasler_GabrielOliveira_etal_IOC_2021.pdf6771e03db38ccf6a74af02260d533e3fMD52TEXTMArianeHasler_GabrielOliveira_etal_IOC_2021.pdf.txtMArianeHasler_GabrielOliveira_etal_IOC_2021.pdf.txtExtracted texttext/plain53366https://www.arca.fiocruz.br/bitstream/icict/48979/3/MArianeHasler_GabrielOliveira_etal_IOC_2021.pdf.txt1062436739bb6362c38b2d299247d6e3MD53icict/489792021-09-04 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dc.title.pt_BR.fl_str_mv Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
title Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
spellingShingle Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
Rocha-Hasler, Marianne
Doença de Chagas
Trypanosoma cruzi
Cloridrato de tomatidina
Inibidor da biossíntese de lipídios
Combinação de drogas
Chagas Disease
Tomatidine hydrochloride
Drug combination
Trypanosoma cruzi
Lipid biosynthesis inhibitor
title_short Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
title_full Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
title_fullStr Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
title_full_unstemmed Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
title_sort Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
author Rocha-Hasler, Marianne
author_facet Rocha-Hasler, Marianne
Oliveira, Gabriel Melo de
Gama, Aline Nefertiti da
Fiuza, Ludmila Ferreira de Almeida
Fesser, Anna Frieda
Cal, Monica
Rocchetti, Romina
Peres, Raiza Brandão
Guan, Xue Li
Kaiser, Marcel
Soeiro, Maria de Nazaré Correia
Mässer, Pascal
author_role author
author2 Oliveira, Gabriel Melo de
Gama, Aline Nefertiti da
Fiuza, Ludmila Ferreira de Almeida
Fesser, Anna Frieda
Cal, Monica
Rocchetti, Romina
Peres, Raiza Brandão
Guan, Xue Li
Kaiser, Marcel
Soeiro, Maria de Nazaré Correia
Mässer, Pascal
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Rocha-Hasler, Marianne
Oliveira, Gabriel Melo de
Gama, Aline Nefertiti da
Fiuza, Ludmila Ferreira de Almeida
Fesser, Anna Frieda
Cal, Monica
Rocchetti, Romina
Peres, Raiza Brandão
Guan, Xue Li
Kaiser, Marcel
Soeiro, Maria de Nazaré Correia
Mässer, Pascal
dc.subject.other.pt_BR.fl_str_mv Doença de Chagas
Trypanosoma cruzi
Cloridrato de tomatidina
Inibidor da biossíntese de lipídios
Combinação de drogas
topic Doença de Chagas
Trypanosoma cruzi
Cloridrato de tomatidina
Inibidor da biossíntese de lipídios
Combinação de drogas
Chagas Disease
Tomatidine hydrochloride
Drug combination
Trypanosoma cruzi
Lipid biosynthesis inhibitor
dc.subject.en.pt_BR.fl_str_mv Chagas Disease
Tomatidine hydrochloride
Drug combination
Trypanosoma cruzi
Lipid biosynthesis inhibitor
description Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil / Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland.
publishDate 2021
dc.date.accessioned.fl_str_mv 2021-09-03T19:41:50Z
dc.date.available.fl_str_mv 2021-09-03T19:41:50Z
dc.date.issued.fl_str_mv 2021
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv ROCHA-HASLER, Marianne et al. Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi. Front. Cell. Infect. Microbiol., v. 11, Article 617917, 11 p, Mar. 2021.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/48979
dc.identifier.issn.pt_BR.fl_str_mv 2235-2988
dc.identifier.doi.none.fl_str_mv 10.3389/fcimb.2021.617917
identifier_str_mv ROCHA-HASLER, Marianne et al. Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi. Front. Cell. Infect. Microbiol., v. 11, Article 617917, 11 p, Mar. 2021.
2235-2988
10.3389/fcimb.2021.617917
url https://www.arca.fiocruz.br/handle/icict/48979
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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