Alterations in membrane fluidity, lipid metabolism, mitochondrial activity, and lipophosphoglycan expression in pentamidine-resistant Leishmania.
Cytoplasmic and mitochondrial membranes were studied in wild-type promastigotes of Leishmania donovani and L. amazonensis treated with pentamidine and in the parasites resistant to this drug. Analyses by flow cytometry showed membrane fluidification in resistant cells and a modification of the lipidic metabolism in pentamidine-treated cells and in resistant clones as compared with wild-type ones. Pentamidine decreased the amounts of membrane polar lipids, i.e., phospholipids, and neutral lipidic droplets in the cytoplasm. Perturbation of lipid constituents did not induce modifications of membrane acid phosphatase and protease activities. Lipophosphoglycan, the major cell-surface glycoconjugate, was no longer detected by Western blotting in resistant cells. The use of rhodamine 123 showed a decrease in transmembrane mitochondrial potential in wild-type cells treated with pentamidine and in resistant parasites. In conclusion, cytoplasmic and mitochondrial membranes and lipidic metabolism are altered in pentamidine-resistant parasites.
Basselin
M
M
Institut de Chimie des Substances Naturelles, C.N.R.S., Gif-sur-Yvette, France.
Robert-Gero
M
M
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D010450:Endopeptidases / Q000378:metabolism; D006028:Glycosphingolipids / Q000096:biosynthesis; D007893:Leishmania donovani / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism; D008560:Membrane Fluidity / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D010419:Pentamidine / Q000494:pharmacology*
D000981:Antiprotozoal Agents; D006028:Glycosphingolipids; C008290:lipophosphonoglycan; D010419:Pentamidine; D010088:Oxidoreductases; D000135:Acid Phosphatase; D010450:Endopeptidases