Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , |
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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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 |
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https://www.arca.fiocruz.br/handle/icict/48979 |
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eng |
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eng |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Frontiers Media |
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Frontiers Media |
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