Characterization of the Disulfiram effect in Trypanosoma cruzi

• Grant number: 13/18970-6
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2014
• End date: September 30, 2016
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Ariel Mariano Silber
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Carsten Wrenger

Abstract

This proposal aims to elucidate the mechanism(s) involved in the trypanocidal effect exhibited by the tetraethylthiuram disulfide drug, - commercially known as Disulfiram ® (herein named as DSF), on the parasite causing of Chagas's disease, the Trypanosoma cruzi. The DSF is susceptible to metabolic breakdown, and therefore their metabolic derivatives will be also analysed; so it will be named as DSF-effect. The inhibitory effect of DSF on both proliferative and infective forms of T. cruzi had been already observed by our group, thus provided some results that we consider as relevant to further approach. In addition, we have seen that DSF impairs the specific activity on the mitochondrial enzyme delta-1-pyrroline-5-carboxylate dehydrogenase; the second enzyme of proline's breakdown pathway. This fact suggests that, the proline metabolism impairment leads in parasite growth diminution through mechanisms not well established so far. Considering the intraspecific variability presented in T. cruzi, we will address to evaluate the DSF-effect on both proliferative and infective forms coming from distinct strains of T. cruzi. The DSF-effect will also be evaluated in the experimental infection in mice. Once it has been completed, we will characterize the type of cell death thereby involved. Our previous data suggest that DSF is active within parasite's mitochondrion, and thus some mitochondrial functions, upon DSF-effect, will be also evaluated. In parallel, aiming to unveil the pathways and/or metabolic targets involved in the DSF-effect, we also intend to perform a metabolomic analysis. These data in together will provide relevant information regarding the alternative use of FDA-approved drugs, and thus might validate mitochondrial metabolic pathways as prompt targets for efficient drug design against Chagas disease. ENUNCIADO DO PROBLEMA (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BARISON, MARIA JULIA; RAPADO, LUDMILA NAKAMURA; MERINO, EMILIO F.; FURUSHO PRAL, ELIZABETH MIEKO; MANTILLA, BRIAN SUAREZ; MARCHESE, LETICIA; NOWICKI, CRISTINA; SILBER, ARIEL MARIANO; CASSERA, MARIA BELEN. Metabolomic profiling reveals a finely tuned, starvation-induced metabolic switch in Trypanosoma cruzi epimastigotes. Journal of Biological Chemistry, v. 292, n. 21, p. 8964-8977, MAY 26 2017. (16/06034-2, 13/18970-6)

MANTILLA, BRIAN S.; PAES, LISVANE S.; PRAL, ELIZABETH M. F.; MARTIL, DAIANA E.; THIEMANN, OTAVIO H.; FERNANDEZ-SILVA, PATRICIO; BASTOS, ERICK L.; SILBER, ARIEL M.. Role of Delta(1)-Pyrroline-5-Carboxylate Dehydrogenase Supports Mitochondrial Metabolism and Host-Cell Invasion of Trypanosoma cruzi. Journal of Biological Chemistry, v. 290, n. 12, p. 7767-7790, MAR 20 2015. (13/18970-6)

MANCHOLA, NUBIA C.; RAPADO, LUDMILA N.; BARISON, MARIA J.; SILBER, ARIEL M.. Biochemical Characterization of Branched Chain Amino Acids Uptake in Trypanosoma cruzi. Journal of Eukaryotic Microbiology, v. 63, n. 3, p. 299-308, MAY-JUN 2016. (13/18970-6)

MERLI, MARCELO L.; PAGURA, LUCAS; HERNANDEZ, JOSEFINA; JULIA BARISON, MARIA; PRAL, ELIZABETH M. F.; SILBER, ARIEL M.; CRICCO, JULIA A.. The Trypanosoma cruzi Protein TcHTE Is Critical for Heme Uptake. PLoS Neglected Tropical Diseases, v. 10, n. 1, JAN 2016. (13/18970-6)

GIRARD, RICHARD M. B. M.; CRISPIM, MARCELL; STOLIC, IVANA; DAMASCENO, FLAVIA SILVA; DA SILVA, MARCELO SANTOS; FURUSHO PRAL, EIZABETH MIEKO; ELIAS, MARIA CAROLINA; BAJIC, MIROSLAV; SILBER, ARIEL MARIANO. An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells. Antimicrobial Agents and Chemotherapy, v. 60, n. 10, p. 5867-5877, OCT 2016. (13/07467-1, 13/18970-6)

BARISON, M. J.; DAMASCENO, F. S.; MANTILLA, B. S.; SILBER, A. M.. The active transport of histidine and its role in ATP production in Trypanosoma cruzi. Journal of Bioenergetics and Biomembranes, v. 48, n. 4, p. 437-449, AUG 2016. (13/18970-6)

GALVEZ ROJAS, ROBERT L.; AHN, IL-YOUNG; MANTILLA, BRIAN SUAREZ; SANT'ANNA, CELSO; FURUSHO PRAL, ELIZABETH MIEKO; SILBER, ARIEL MARIANO. The Uptake of GABA in Trypanosoma cruzi. Journal of Eukaryotic Microbiology, v. 62, n. 5, p. 629-636, SEP-OCT 2015. (13/18970-6)

MANCHOLA, NUBIA CAROLINA; SILBER, ARIEL MARIANO; NOWICKI, CRISTINA. The Non-Canonical Substrates of Trypanosoma cruzi Tyrosine and Aspartate Aminotransferases: Branched-Chain Amino Acids. Journal of Eukaryotic Microbiology, v. 65, n. 1, p. 70-76, JAN-FEB 2018. (13/18970-6, 16/06034-2)

SANTOS SOUZA, HIGO FERNANDO; REAL, DANIEL; LEONARDI, DARIO; ROCHA, SANDRA CARLA; ALONSO, VICTORIA; SERRA, ESTEBAN; SILBER, ARIEL MARIANO; JAVIER SALOMON, CLAUDIO. Development andin vitro/in vivoevaluation of a novel benznidazole liquid dosage form using a quality-by-design approach. TROPICAL MEDICINE & INTERNATIONAL HEALTH, v. 22, n. 12, p. 1514-1522, DEC 2017. (16/06034-2, 13/18970-6)