title: Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo.
abstract: Miltefosine (hexadecylphosphocholine) is the first oral antileishmanial drug. In this study, we addressed the question whether miltefosine-resistant Leishmania donovani promastigotes transform to miltefosine-resistant amastigotes. A promastigote line, M-mutR, showed defective internalisation of miltefosine owing to mutations in LdMT, similar to previously described resistant lines. M-mutR parasites were infective to macrophages in vitro as well as in BALB/c mice in vivo. There was good correlation of in vitro resistance indices between promastigotes and intracellular amastigotes. Most importantly, M-mutR parasites retained the resistant phenotype in vivo, with no decrease of hepatic burden in BALB/c mice following miltefosine treatment up to 30 mg/kg (ca. 90% inhibition in wild-type infections). No cross-resistance to other antileishmanial drugs was observed in M-mutR amastigotes.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. karin.seifert@lshtm.ac.uk
authors.forename: Karin
authors.initials: K
authors.lastname: Seifert
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Pérez-Victoria
authors.forename: Marianne
authors.initials: M
authors.lastname: Stettler
authors.forename: María P
authors.initials: MP
authors.lastname: Sánchez-Cañete
authors.forename: Santiago
authors.initials: S
authors.lastname: Castanys
authors.forename: Francisco
authors.initials: F
authors.lastname: Gamarro
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000981:Antiprotozoal Agents / Q000378:metabolism* / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D005838:Genotype; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015800:Protozoan Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D000981:Antiprotozoal Agents; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D010767:Phosphorylcholine; C039128:miltefosine; D000251:Adenosine Triphosphatases; C480230:miltefosine transporter, Leishmania donovani