Overexpression of eukaryotic initiation factor 5A (eIF5A) affects susceptibility to benznidazole in Trypanosoma cruzi populations

• Published in: Memórias do Instituto Oswaldo Cruz Vol. 113; no. 9; p. e180162
• Main Authors: Moreira, Douglas de Souza, Duarte, Ana Paula, Pais, Fabiano Sviatopolk Mirsky, Silva-Pereira, Rosiane Aparecida da, Romanha, Alvaro José, Schenkman, Sergio, Murta, Silvane Maria Fonseca
• Format: Journal Article
• Language: English
• Published: Brazil Instituto Oswaldo Cruz, Ministério da Saúde 26-07-2018; Fundação Oswaldo Cruz (FIOCRUZ)
• Subjects: benznidazole; drug resistance; Drug Resistance - genetics; eukaryotic initiation factor 5A (eIF5A); Eukaryotic Translation Initiation Factor 5A; Gene Expression; Humans; Nitroimidazoles - pharmacology; PARASITOLOGY; Peptide Initiation Factors - analysis; Peptide Initiation Factors - drug effects; Peptide Initiation Factors - metabolism; RNA-Binding Proteins - analysis; RNA-Binding Proteins - drug effects; RNA-Binding Proteins - metabolism; Short Communication; TROPICAL MEDICINE; Trypanocidal Agents - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Trypanosoma cruzi - genetics; drug resistance; eukaryotic initiation factor 5A (eIF5A); benznidazole; Trypanosoma cruzi
• ISSN: 0074-0276; 1678-8060; 1678-8060
• DOI: 10.1590/0074-02760180162

Eukaryotic initiation factor 5A (eIF5A) is a conserved protein with an essential role in translation elongation. Using one and two-dimensional western blotting, we showed that the eIF5A protein level was 2-fold lower in benznidazole (BZ)-resistant (BZR and 17LER) Trypanosoma cruzi populations than in their respective susceptible counterparts (BZS and 17WTS). To confirm the role of eIF5A in BZ resistance, we transfected BZS and 17WTS with the wild-type eIF5A or mutant eIF5A-S2A (in which serine 2 was replaced by alanine). Upon overexpressing eIF5A, both susceptible lines became approximately 3- and 5-fold more sensitive to BZ. In contrast, the eIF5A-S2A mutant did not alter its susceptibility to BZ. These data suggest that BZ resistance might arise from either decreasing the translation of proteins that require eIF5A, or as a consequence of differential levels of precursors for the hypusination reactions (e.g., spermidine and trypanothione), both of which alter BZ's effects in the parasite.