Leishmania donovani Resistance to Miltefosine Involves a Defective Inward Translocation of the Drug

AUTOR(ES)

Pérez-Victoria, F. Javier

FONTE

American Society for Microbiology

RESUMO

Miltefosine (hexadecylphosphocholine [HePC]) is the first drug approved for the oral treatment of visceral leishmaniasis. As part of a study on the mechanisms of action of this drug and on the rates of resistance to this drug, we have been working in vitro with an Leishmania donovani line that was previously shown to be 15-fold more resistant to HePC. We have studied the accumulation of [14C]HePC by L. donovani promastigotes and have found a drastic reduction (>95%) in the ability of the resistant line to internalize the drug. Binding of HePC to the plasma membrane and drug efflux from preloaded cells were similar in both drug-sensitive and -resistant lines, and no [14C]HePC metabolism was evident in either line. Resistant parasites were also unable to take up other short-chain phospholipid analogs, independently of their polar head group, even though endocytosis remained unaltered. Finally, HePC uptake was temperature and energy dependent and sensitive to the thiol-reactive agent N-ethylmaleimide. We propose that inward translocation of a short-chain phospholipid across the plasma membrane may exist in Leishmania promastigotes and that such activity is defective in the resistant line.

Documentos Relacionados

• Possible Mechanism of Miltefosine-Mediated Death of Leishmania donovani†
• Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion
• Miltefosine Induces Apoptosis-Like Death in Leishmania donovani Promastigotes
• Point mutations in a nucleoside transporter gene from Leishmania donovani confer drug resistance and alter substrate selectivity
• Activities of Hexadecylphosphocholine (Miltefosine), AmBisome, and Sodium Stibogluconate (Pentostam) against Leishmania donovani in Immunodeficient scid Mice