Your browser doesn't support javascript.
loading
Discovery of factors linked to antimony resistance in Leishmania panamensis through differential proteome analysis.
Walker, John; Gongora, Rafael; Vasquez, Juan-José; Drummelsmith, Jolyne; Burchmore, Richard; Roy, Gaetan; Ouellette, Marc; Gomez, Maria Adelaida; Saravia, Nancy G.
Afiliação
  • Walker J; Centro Internacional de Entrenamiento e Investigaciones Medicas, Carrera 125, No. 19-225, Cali, Colombia.
Mol Biochem Parasitol ; 183(2): 166-76, 2012 Jun.
Article em En | MEDLINE | ID: mdl-22449941
ABSTRACT
The rate of treatment failure to antileishmanial chemotherapy in Latin America is up to 64%. Parasite drug resistance contributes to an unknown proportion of treatment failures. Identification of clinically relevant molecular mechanisms responsible for parasite drug resistance is critical to the conservation of available drugs and to the discovery of novel targets to reverse the resistant phenotype. We conducted comparative proteomic-based analysis of Leishmania (Viannia) panamensis lines selected in vitro for resistance to trivalent antimony (Sb(III)) to identify factors associated with antimony resistance. Using 2-dimensional gel electrophoresis, two distinct sub-proteomes (soluble in NP-40/urea and Triton X-114, respectively) of promastigotes of WT and Sb(III)-resistant lines were generated. Overall, 9 differentially expressed putative Sb-resistance factors were detected and identified by mass spectrometry. These constituted two major groups (a) proteins involved in general stress responses and (b) proteins with highly specific metabolic and transport functions, potentially directly contributing to the Sb-resistance mechanism. Notably, the sulfur amino acid-metabolizing enzymes S-adenosylmethionine synthetase (SAMS) and S-adenosylhomocysteine hydrolase (SAHH) were over-expressed in Sb(III)-resistant lines and Sb(III)-resistant clinical isolates. These enzymes play a central role in the upstream synthesis of precursors of trypanothione, a key molecule involved in Sb-resistance in Leishmania parasites, and suggest involvement of epigenetic regulation in response to drug exposure. These data re-enforce the importance of thiol metabolism in Leishmania Sb resistance, reveal previously unrecognized steps in the mechanism(s) of Sb tolerance, and suggest a cross-talk between drug resistance, metabolism and virulence.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistência Microbiana a Medicamentos / Proteínas de Protozoários / Leishmania guyanensis / Proteoma / Antimônio / Antiprotozoários Tipo de estudo: Prognostic_studies Limite: Humans País como assunto: America central / Panama Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Resistência Microbiana a Medicamentos / Proteínas de Protozoários / Leishmania guyanensis / Proteoma / Antimônio / Antiprotozoários Tipo de estudo: Prognostic_studies Limite: Humans País como assunto: America central / Panama Idioma: En Ano de publicação: 2012 Tipo de documento: Article