New insights into the mechanistic action of methyldehydrodieugenol B towards Leishmania (L.) infantum via a multiplatform based untargeted metabolomics approach

Autor(es)

Baptista Canuto, Gisele Andre ; Dorr, Fabiane ; Ghilardi Lago, Joao Henrique ; Tempone, Andre Gustavo ; Pinto, Ernani ; Pimenta, Daniel Carvalho ; Simon Farah, Joao Pedro ; Manso Alves, Maria Julia ; Maggi Tavares, Marina Franco

• Tipo de documento: Artigo Científico
• Fonte: METABOLOMICS; v. 13, n. 5 MAY 2017.
• Citações Web of Science: 2

Resumo

Introduction Leishmaniasis is a parasitic neglected disease affecting millions of people worldwide. Clinical practice resorts to long and costly treatments with a therapeutic arsenal limited to highly toxic drugs, often associated to adverse side effects. Additionally, resistant strains are reported to be increasing. Aim In this work, the mechanistic action of a drug candidate (methydehydrodieugenol B), isolated from twigs of Nectandra leucantha, towards Leishmania infantum was studied by a global metabolomics approach using GC-MS and RPLC-MS platforms. Method L. infantum promastigotes were grown in culture medium for 72 h and treated with methydehydrodieugenol B at 58.18 mu g. mL(-1) concentration; after 48 h treatment, enzyme activity was quenched, cells washed and frozen until analysis. For GC-MS analysis (Fiehn's method), 1: 1 methanol: water extracts were prepared and derivatized with O-methoxyamine in pyridine at room temperature for 90 min, followed by silylation with BSTFA/1% TMCS at 40 degrees C for 30 min. Pure methanolic extracts were also prepared and analyzed directly by RPLC-MS with a acetonitrile/water mobile phase acidulated with formic acid and gradient elution. Result Several amino acids, fatty acids, carbohydrates, and glycerolipids were found as discriminant metabolites, mostly decreased in treated samples. Due to the complexity of the parasite metabolism and the great diversity of altered metabolites, a multi-target mechanism was assigned to the drug candidate, where changes in the cell energy sources and in the lipid composition of the parasite plasma membrane were prominent. Conclusion These results contributed to elucidate the broad action of methyldehydrodieugenol B against Leishmania, paving the way in the search of novel alternative therapies. (AU)

• Processo FAPESP: 15/50075-2 - Brazilian biodiversity as a source for novel drug scaffolds against neglected protozoan diseases
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/04601-6 - Avaliaçao metabolômica comparativa in vitro de fármacos candidatos ao tratamento de leishmaniose
• Beneficiário: Gisele André Baptista Canuto
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/25494-9 - Resposta de Trypanosoma cruzi ao meio ambiente: matriz extracelular e mudanças de pH
• Beneficiário: Maria Julia Manso Alves
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/07361-6 - Modulação de mobilidade em eletroforese capilar
• Beneficiário: Marina Franco Maggi Tavares
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/18756-1 - Avaliação de novas alternativas terapêuticas com fármacos sintéticos em modelos in vitro e experimentais de Leishmania (L.) infantum chagasi
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular