Mechanisms of action and resistance to miltefosine in Leishmania spp.

Abstract

Leishmania spp. are parasitic protozoa responsible for a complex of diseases known as leishmaniasis. The treatment of all clinical forms of leishmaniasis relies on costly parenteral administered drugs with multiple undesirable effects. The main drugs available for the treatment of leishmaniasis in Brazil are pentavalent antimony, anfotericin B and pentamidine. Clinical failure after treatment with antimony has been increasingly reported. Recently, the effectiveness of miltefosine in the treatment of visceral leishmaniasis was described and the drug is currently in use mainly for visceral leishmaniasis in Asia and Europe. However, the knowledge about miltefosine's mechanisms of action and resistance and the cellular targets in the parasite is limited. New World Leishmania species are known to be less sensitive to miltefosine than Old World parasites but data on in vitro sensitivity of Leishmania isolates from Brazilian patients is not available. In this project we propose to evaluate the sensitivity of field isolates from Brazil to miltefosine. Based on previous studies, we also intend to characterize a putative phospholipid transporter that is found only in the L. (V.) braziliensis genome and not in other Leishmania species and to generate miltefosine resistant mutants of the Leishmania species endemic in Brazil, aiming to identify potential genes associated to the mechanism of drug resistance. Our study will contribute in the evaluation of miltefosine's potential to be included in the chemotherapeutic arsenal in Brazil and will contribute in the understanding of the mechanisms of action and resistance for this drug and in the identification of potential molecular markers related to miltefosine resistance in Leishmania spp. from Brazil.