Investigation of the pathways related to intrinsic miltefosine tolerance in Leishmania (Viannia) braziliensis clinical isolates reveals differences in drug uptake

Publication date: Available online 25 February 2019Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): Caroline R. Espada, Rubens M. Magalhães, Mario C. Cruz, Paulo R. Machado, Albert Schriefer, Edgar M. Carvalho, Valentín Hornillos, João M. Alves, Angela K. Cruz, Adriano C. Coelho, Silvia R.B. UlianaAbstractIn Brazil, cutaneous leishmaniasis is caused predominantly by L. (V.) braziliensis. The few therapeutic drugs available exhibit several limitations, mainly related to drug toxicity and reduced efficacy in some regions. Miltefosine (MF), the only oral drug available for leishmaniasis treatment, is not widely available and has not yet been approved for human use in Brazil. Our group previously reported the existence of differential susceptibility among L. (V.) braziliensis clinical isolates. In this work, we further characterized three of these isolates of L. (V.) braziliensis chosen because they exhibited the lowest and the highest MF half maximal inhibitory concentrations and were therefore considered less tolerant or more tolerant, respectively. Uptake of MF, and also of phosphocholine, were found to be significantly different in more tolerant parasites compared to the less sensitive isolate, which raised the hypothesis of differences in the MF transport complex Miltefosine Transporter (MT)-Ros3. Although some polymorphisms in those genes were found, they did not correlate with the drug susceptibility phenotype. Drug efflux and compartm...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research