| Author | Rocha-Hasler, Marianne | |
| Author | Oliveira, Gabriel Melo de | |
| Author | Gama, Aline Nefertiti da | |
| Author | Fiuza, Ludmila Ferreira de Almeida | |
| Author | Fesser, Anna Frieda | |
| Author | Cal, Monica | |
| Author | Rocchetti, Romina | |
| Author | Peres, Raiza Brandão | |
| Author | Guan, Xue Li | |
| Author | Kaiser, Marcel | |
| Author | Soeiro, Maria de Nazaré Correia | |
| Author | Mässer, Pascal | |
| Access date | 2021-09-03T19:41:50Z | |
| Available date | 2021-09-03T19:41:50Z | |
| Document date | 2021 | |
| Citation | 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. | pt_BR |
| ISSN | 2235-2988 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/48979 | |
| Language | eng | pt_BR |
| Publisher | Frontiers Media | pt_BR |
| Rights | open access | |
| Subject in Portuguese | Doença de Chagas | pt_BR |
| Subject in Portuguese | Trypanosoma cruzi | pt_BR |
| Subject in Portuguese | Cloridrato de tomatidina | pt_BR |
| Subject in Portuguese | Inibidor da biossíntese de lipídios | pt_BR |
| Subject in Portuguese | Combinação de drogas | pt_BR |
| Title | Combination With Tomatidine Improves the Potency of Posaconazole Against Trypanosoma cruzi | pt_BR |
| Type | Article | |
| DOI | 10.3389/fcimb.2021.617917 | |
| Abstract | 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. | pt_BR |
| Affilliation | 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. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Systems Biology of Lipid Metabolism in Human Health and Diseases Laboratory, Lee Kong Chian School of Medicine. Singapore, Singapore. | pt_BR |
| Affilliation | Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Medical Parasitology and Infection Biology. Basel, Switzerland / University of Basel. Basel, Switzerland. | pt_BR |
| Subject | Chagas Disease | pt_BR |
| Subject | Tomatidine hydrochloride | pt_BR |
| Subject | Drug combination | pt_BR |
| Subject | Trypanosoma cruzi | pt_BR |
| Subject | Lipid biosynthesis inhibitor | pt_BR |
| xmlui.metadata.dc.subject.ods | 03 Saúde e Bem-Estar | |
