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 internalisatio...

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Bibliographic Details
Published in:International journal of antimicrobial agents 2007-09, Vol.30 (3), p.229-235
Main Authors: Seifert, Karin, Pérez-Victoria, F. Javier, Stettler, Marianne, Sánchez-Cañete, María P, Castanys, Santiago, Gamarro, Francisco, Croft, Simon L
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - genetics
Adenosine Triphosphatases - physiology
Animals
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiprotozoal Agents - metabolism
Antiprotozoal Agents - pharmacology
Biological and medical sciences
Drug Resistance
Female
Genotype
Infectious Disease
Leishmania donovani
Leishmania donovani - drug effects
Leishmaniasis, Visceral - drug therapy
Leishmaniasis, Visceral - microbiology
Medical sciences
Membrane Transport Proteins - genetics
Membrane Transport Proteins - physiology
Mice
Mice, Inbred BALB C
Miltefosine
Mutation - physiology
P-type ATPase
Pharmacology. Drug treatments
Phenotype
Phospholipid translocase
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - metabolism
Phosphorylcholine - pharmacology
Protozoan Proteins - genetics
Protozoan Proteins - physiology
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Summary: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.
ISSN:0924-8579
1872-7913
DOI:10.1016/j.ijantimicag.2007.05.007