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Antimicrobial Agents and Chemotherapy, April 2009, p. 1305-1313, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01694-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Low Plasma Membrane Expression of the Miltefosine Transport Complex Renders Leishmania braziliensis Refractory to the Drug {triangledown}

María P. Sánchez-Cañete, Luís Carvalho, F. Javier Pérez-Victoria,{dagger} Francisco Gamarro,* and Santiago Castanys*

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

Received 22 December 2008/ Returned for modification 9 January 2009/ Accepted 23 January 2009

Miltefosine (hexadecylphosphocholine, MLF) is the first oral drug with recognized efficacy against both visceral and cutaneous leishmaniasis. However, some clinical studies have suggested that MLF shows significantly less efficiency against the cutaneous leishmaniasis caused by Leishmania braziliensis. In this work, we have determined the cellular and molecular basis for the natural MLF resistance observed in L. braziliensis. Four independent L. braziliensis clinical isolates showed a marked decrease in MLF sensitivity that was due to their inability to internalize the drug. MLF internalization in the highly sensitive L. donovani species requires at least two proteins in the plasma membrane, LdMT, a P-type ATPase involved in phospholipid translocation, and its β subunit, LdRos3. Strikingly, L. braziliensis parasites showed highly reduced levels of this MLF translocation machinery at the plasma membrane, mainly because of the low expression levels of the β subunit, LbRos3. Overexpression of LbRos3 induces increased MLF sensitivity not only in L. braziliensis promastigotes but also in intracellular amastigotes. These results further highlight the importance of the MLF translocation machinery in determining MLF potency and point toward the development of protocols to routinely monitor MLF susceptibility in geographic areas where L. braziliensis might be prevalent.

* Corresponding author. Mailing address for Santiago Castanys: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. Phone: 34 958 181666. Fax: 34 958 181632. E-mail: castanys{at}ipb.csic.es. Mailing address for Francisco Gamarro: Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18100 Armilla, Granada, Spain. Phone: 34 958 181667. Fax: 34 958 181632. E-mail: gamarro{at}ipb.csic.es

{triangledown} Published ahead of print on 2 February 2009.

{dagger} Present address: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.

Antimicrobial Agents and Chemotherapy, April 2009, p. 1305-1313, Vol. 53, No. 4
0066-4804/09/$08.00+0     doi:10.1128/AAC.01694-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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