Inactivation of the miltefosine transporter, LdMT, causes miltefosine resistance that is conferred to the amastigote stage of Leishmania donovani and persists in vivo

• Published in: International journal of antimicrobial agents Vol. 30; no. 3; pp. 229 - 235
• Main Authors: Seifert, Karin, Pérez-Victoria, F. Javier, Stettler, Marianne, Sánchez-Cañete, María P, Castanys, Santiago, Gamarro, Francisco, Croft, Simon L
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 01.09.2007; Amsterdam Elsevier; New York, NY
• 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; Miltefosine; Phospholipid translocase; Drug resistance; P-type ATPase; Leishmania donovani; Antineoplastic agent; Kinetoplastida; Protozoa; Treatment resistance; Enzyme; Adenosinetriphosphatase; Phospholipid; Inactivation; In vivo; Clinical stage; Lysophospholipid; Hydrolases; Amastigote; Carrier protein
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2007.05.007

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.