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

  • Espada, Caroline R1
  • Magalhães, Rubens M2
  • Cruz, Mario C3
  • Machado, Paulo R4
  • Schriefer, Albert5
  • Carvalho, Edgar M6
  • Hornillos, Valentín7
  • Alves, João M1
  • Cruz, Angela K2
  • Coelho, Adriano C1
  • Uliana, Silvia R B8
  • 1 Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil. , (Brazil)
  • 2 Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil. , (Brazil)
  • 3 Centro de Facilidades para Apoio a Pesquisa, CEFAP-USP, Universidade de São Paulo, São Paulo, Brazil. , (Brazil)
  • 4 Serviço de Imunologia, HUPES, Universidade Federal da Bahia, Salvador, Brazil. , (Brazil)
  • 5 Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Brazil. , (Brazil)
  • 6 Serviço de Imunologia, HUPES, Universidade Federal da Bahia, Salvador, Brazil; Centro de Pesquisas Gonçalo Moniz, Fiocruz-Bahia, Salvador, Brazil. , (Brazil)
  • 7 Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Sevilla, Spain. , (Spain)
  • 8 Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil. Electronic address: [email protected] , (Brazil)
Published Article
International journal for parasitology. Drugs and drug resistance
Publication Date
Dec 01, 2019
DOI: 10.1016/j.ijpddr.2019.02.005
PMID: 30850347


In 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 compartmentalization were similar in the isolates tested, and amphotericin B susceptibility was retained in MF tolerant parasites, suggesting that increased fitness was also not the basis of observed differences. Transcriptomic analysis revealed that Ros3 mRNA levels were upregulated in the sensitive strain compared to the tolerant ones. Increased mRNA abundance in more tolerant isolates was validated by quantitative PCR. Our results suggest that differential gene expression of the MT transporter complex is the basis of the differential susceptibility in these unselected, naturally occurring parasites. Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

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