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

Pérez-Victoria, F. Javier; Sánchez-Cañete, María P.; Seifert, Karin; Croft, Simon L.; Sundar, Shyam; Castanys, Santiago; Gamarro, Francisco

doi:10.1016/j.drup.2006.04.001

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Volume 9, Issue 1 , Pages 26-39, February 2006

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

F. Javier Pérez-Victoria
- Instituto de Parasitología y Biomedicina “López-Neyra”, Spanish Research Council (C.S.I.C.), Granada, Spain
María P. Sánchez-Cañete
- Instituto de Parasitología y Biomedicina “López-Neyra”, Spanish Research Council (C.S.I.C.), Granada, Spain
Karin Seifert
- Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
Simon L. Croft
- Drugs for Neglected Diseases Initiative, Geneva, Switzerland
Shyam Sundar
- Kala-azar Medical Research Center, Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
Santiago Castanys
- Instituto de Parasitología y Biomedicina “López-Neyra”, Spanish Research Council (C.S.I.C.), Granada, Spain
- The authors are equal senior investigators in this study.
Francisco Gamarro
- Instituto de Parasitología y Biomedicina “López-Neyra”, Spanish Research Council (C.S.I.C.), Granada, Spain
- The authors are equal senior investigators in this study.
- Corresponding author at: Instituto de Parasitología y Biomedicina “López-Neyra”. C.S.I.C. Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. Tel.: +34 958181667; fax: +34 958181632.

Received 5 November 2005; received in revised form 27 March 2006; accepted 6 April 2006.

Abstract

Miltefosine (hexadecylphosphocholine, MIL), registered as Impavido^®, 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 150h), 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.