Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use


Perez-Victoria, FJ; Sanchez-Canete, MP; Seifert, K; Croft, SL; Sundar, S; Castanys, S; Gamarro, F; (2006) Mechanisms of experimental resistance of Leishmania to miltefosine: Implications for clinical use. Drug resistance updates , 9 (1-2). pp. 26-39. ISSN 1368-7646 DOI: 10.1016/j.drup.2006.04.001

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Abstract

Miltefosine (hexadecylphosphocholine, MIL), registered as Impavido((R)), has become the first oral drug for the treatment of visceral and cutaneous leishmanasis. MIL is a simple molecule, very stable, relatively safe and highly efficient in clinical trials. However, MIL requires a long treatment course (28 days) and has a long half-life (around 150 h), which might accelerate the emergence of drug resistance in case of inadequate use. The mechanisms of MIL resistance have been studied in vitro with experimental resistant lines. Resistance was shown to develop quickly in Leishmania promastigotes. Interestingly, a decreased MIL accumulation has always accounted for the resistance phenotype. The lower MIL accumulation can be achieved by two independent mechanisms: (i) an increase in drug efflux, mediated by the overexpression of the ABC transporter P-glycoprotein, and (ii) a decrease in drug uptake, which is easily achieved by the inactivation of any one of the two proteins known to be responsible for the MIL uptake, the MIL transporter LdMT and its beta subunit LdRos3. Policies concerning a proper use of this drug should be followed and supervised by health authorities of endemic areas to minimalize the risk for the appearance of drug failures and to ensure a long life span for this effective oral drug. (c) 2006 Elsevier Ltd. All rights reserved.

Item Type: Article
Keywords: Leishmania, miltefosine, experimental drug resistance, aminophospholipid translocase, CDC50 family, control, drug, combinations, LdMT, LdRos3, Indian visceral leishmaniasis, plus sodium stibogluconate, yeast, plasma-membrane, p-type atpases, hexadecylphosphocholine miltefosine, oral miltefosine, in-vitro, donovani promastigotes, drug-resistance, cell-lines
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Antimicrobial Resistance Centre (AMR)
Leishmaniasis Group
PubMed ID: 16814199
Web of Science ID: 239125900003
URI: http://researchonline.lshtm.ac.uk/id/eprint/11617

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