Susceptibility to miltefosine in Leishmania (Viannia) braziliensis clinical isolates: phenotypic characterization and investigation of the basis involved in reduced susceptibility to the drug

Abstract

Leishmania (Viannia) braziliensis is the main etiological agent of Cutaneous Leishmaniasis in Brazil, where in 2014 approximately 21,000 new cases of the disease were notified. The arsenal available for treatment is limited due to parenteral administration, toxicity, high cost, and emergence of resistance. Miltefosine is the only oral drug approved for the treatment of Cutaneous and Visceral Leishmaniasis and it is in use in Colombia and India. Only two clinical trials evaluating the efficacy of miltefosine for Cutaneous Leishmaniasis in Brazil were performed and in both, miltefosine was more active than pentavalent antimonials. Nevertheless, miltefosine is not yet approved for Leishmaniasis treatment in Brazil and there are no studies on the susceptibility of Brazilian clinical isolates to this drug. Thus, the aim of this project is to evaluate the susceptibility of L. (V.) braziliensis clinical isolates, obtained from patients of two different regions of Brazil, to miltefosine and to elucidate the molecular bases implicated on differential susceptibility to this drug in these isolates. The susceptibility to miltefosine was characterized for 17 L. (V.) braziliensis clinical isolates, never exposed to this drug and we found significant differences in effective drug concentrations among different isolates. In order to understand the molecular basis responsible for the differences on miltefosine susceptibility found between the isolates, the influx, accumulation, distribution and efflux of the drug and the nucleotide sequence and gene expression pattern of the genes encoding the miltefosine transporter (MT) and its subunit Ros3 will be determined. (AU)