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Mechanisms of Miltefosine Resistance in Leishmania

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Drug Resistance in Leishmania Parasites

Summary

The use of miltefosine (hexadecylphosphocholine), the first oral drug for the treatment of visceral and cutaneous leishmaniasis, results in high cure rates in geographical areas where antimony resistance is prevalent. Miltefosine is a simple molecule which, if used correctly, is very stable, relatively safe and highly efficient, as shown by numerous clinical trials. However, the major drawbacks of miltefosine include its teratogenic potential and long half-life, which increases the chances of a rapid emergence of resistance. The mechanisms of miltefosine resistance have been studied in vitro using experimental resistant lines. Resistance is easily induced in vitro, with decreased miltefosine uptake being responsible for the resistance phenotype. In these resistant lines, there is inactivation of one of the two proteins known to be responsible for miltefosine uptake, namely the miltefosine transporter LdMT and its beta subunit LdRos3. Furthermore, miltefosine accumulation is reduced by the overexpression of the ABC (ATP-binding cassette) P-glycoprotein/MDR1 and ABC subfamily G members, multidrug exporters which pump the drug out of the cell, thereby mediating miltefosine resistance. Additionally, other factors, such as changes in the plasma membrane lipid composition and overexpression of Hsp80, calpain-like SKCRP14.1, 299 KDa protein, eIF4A or histone H2A have also been suggested to contribute to miltefosine resistance. The current challenge is therefore to identify drug-resistance markers to miltefosine to be implemented in the field as a policy to prevent drug resistance in leishmaniasis.

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  1. Instituto de Parasitología y Biomedicina “López-Neyra”, CSIC (IPBLN-CSIC), Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento s/n 18100 Armilla, Granada, Spain

    Francisco Gamarro, María P. Sánchez-Cañete & Santiago Castanys

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  1. Francisco Gamarro
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  2. María P. Sánchez-Cañete
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  3. Santiago Castanys
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Correspondence to Francisco Gamarro or Santiago Castanys .

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Editors and Affiliations

  1. Fac. Medicina, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas, 1062, Venezuela

    Alicia Ponte-Sucre

  2. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Emilia Diaz

  3. Universidad Central de Venezuela, ciudad universitaria, Caracas, 1062, Venezuela

    Maritza Padrón-Nieves

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© 2013 Springer-Verlag Wien

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Gamarro, F., Sánchez-Cañete, M.P., Castanys, S. (2013). Mechanisms of Miltefosine Resistance in Leishmania . In: Ponte-Sucre, A., Diaz, E., Padrón-Nieves, M. (eds) Drug Resistance in Leishmania Parasites. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1125-3_17

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  • DOI: https://doi.org/10.1007/978-3-7091-1125-3_17

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  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-0238-1

  • Online ISBN: 978-3-7091-1125-3

  • eBook Packages: MedicineMedicine (R0)

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