Ether-lipid (alkyl-phospholipid) metabolism and the mechanism of action ofether-lipid analogues in Leishmania

Ether-lipid (alkyl-phospholipid) analogues such as Miltefosine possess pote nt in vitro and in vivo anti-leishmanial activity and these compounds are c urrently undergoing clinical trials in humans. These analogues are also eff ective against Trypanosoma cruzi and Trypanosoma brucei subspecies but thei r mode of action is not known. Leishmania have high levels of ether-lipids and these are mainly found in the glycosylphosphatidylinositol-anchored gly colipids and glycoproteins present on the surface of the parasites. In Leis hmania mexicana promastigotes we have studied both the initiating steps for the biosynthesis of ether-lipids, and key remodelling steps. The effect of Miltefosine and Edelfosine, on key enzymes involved in the metabolism of e ther-lipids has been studied. The enzymes include dihydroxyacetonephosphate acyltransferase, sn-1-acyl-2-lyso-glycero-3-phosphocholine and sn-1-alkyl- 2-lyso-glycero-3-phosphocholine acyltransferases. We confirm that the initi ating steps in ether-lipid metabolism in Leishmania are present in glycosom es, and that Miltefosine or Edelfosine did not perturb these enzymes. The m etabolism of the latter phosphatidylcholine base intermediates, which may b e involved in the remodelling of acyl- and alkyl-glycerophospholipids, was also seemingly associated with glycosomes. Both Miltefosine and Edelfosine inhibited this microbody (glycosomal) located alkyl-specific-acyl-CoA acylt ransferase in a dose-dependent manner with an inhibitory concentration of 5 0 muM. It is suggested therefore that a perturbation of ether-lipid remodel ling could be responsible for the anti-leishmanial action of these drugs. ( C) 2000 Elsevier Science B.V. All rights reserved.