Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo.
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.
Seifert
Karin
K
Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. karin.seifert@lshtm.ac.uk
Pérez-Victoria
F Javier
FJ
Stettler
Marianne
M
Sánchez-Cañete
María P
MP
Castanys
Santiago
S
Gamarro
Francisco
F
Croft
Simon L
SL
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
D000981:Antiprotozoal Agents; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D010767:Phosphorylcholine; C039128:miltefosine; D000251:Adenosine Triphosphatases; C480230:miltefosine transporter, Leishmania donovani