Ornithine decarboxylase or gamma-glutamylcysteine synthetase overexpression protects Leishmania (Vianna) guyanensis against antimony.
Trypanosomatids present a unique mechanism for detoxification of peroxides that is dependent on trypanothione (bisglutathionylspermidine). Ornithine decarboxylase (ODC) and γ-glutamylcysteine synthetase (GSH1) produce molecules that are direct precursors of trypanothione. In this study, Leishmania guyanensis odc and gsh1 overexpressor cell lines were generated to investigate the contribution of these genes to the trivalent antimony (SbIII)-resistance phenotype. The ODC- or GSH1-overexpressors parasites presented an increase of two and four-fold in SbIII-resistance index, respectively, when compared with the wild-type line. Pharmacological inhibition of ODC and GSH1 with the specific inhibitors α-difluoromethylornithine (DFMO) and buthionine sulfoximine (BSO), respectively, increased the antileishmanial effect of SbIIIin all cell lines. However, the ODC- and GSH1-overexpressor were still more resistant to SbIIIthan the parental cell line. Together, our data shows that modulation of ODC and GSH1 levels and activity is sufficient to affect L. guyanensis susceptibility to SbIII, and confirms a role of these genes in the SbIII-resistance phenotype.
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil.
Maisa S
MS
Fonseca
Laboratorio de Biología Redox de Tripanosomátidos, Institut Pasteur de Montevideo, Mataojo 2020 11400, Montevideo, Uruguay.
Marcelo A
MA
Comini
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil.
Bethânia V
BV
Resende
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil.
Ana Maria M
AM
Santi
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil.
Antônio P
AP
Zoboli
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil.
Douglas S
DS
Moreira
Laboratório de Parasitologia Celular e Molecular, Centro de Pesquisas René Rachou CPqRR/Fiocruz, Av. Augusto de Lima 1715 301190-002, Belo Horizonte, MG, Brazil. Electronic address: silvane@cpqrr.fiocruz.br.
Silvane M F
SM
Murta
D000818:Animals; D000965:Antimony / Q000494:pharmacology*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D018334:Leishmania guyanensis / Q000187:drug effects* / Q000201:enzymology*; D007897:Leishmaniasis, Mucocutaneous / Q000188:drug therapy; D058069:Neglected Diseases / Q000188:drug therapy / Q000469:parasitology; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D011994:Recombinant Proteins; D019328:Buthionine Sulfoximine; D000965:Antimony; D009955:Ornithine Decarboxylase; D005721:Glutamate-Cysteine Ligase; D000518:Eflornithine
Antimony-resistance; Gamma-glutamylcysteine synthetase; Leishmania guyanensis; Ornithine decarboxylase; Trypanothione