Increased thiol levels in antimony-resistant leishmania infantum isolated from treatment-refractory visceral leishmaniasis in Brazil

Lucas S. Magalhães, Lays G.S. Bomfim, Sthefanne G. Mota, Geydson S. Cruz, Cristiane B. Corrêa, Diego M. Tanajura, Michael W. Lipscomb, Valéria M. Borges, Amélia R. De Jesus, Roque P. De Almeida, Tatiana R. De Moura

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13 Scopus citations

Abstract

BACKGROUND Treatment-refractory visceral leishmaniasis (VL) has become an important problem in many countries. OBJECTIVES We evaluated the antimony-resistance mechanisms of Leishmania infantum isolated from VL patients refractory or responsive to treatment with pentavalent antimony. METHODS Strains isolated from antimony-refractory patients (in vitro antimony-resistant isolates) and antimony-responsive patients (in vitro antimony-sensitive isolates) were examined. Morphological changes were evaluated by transmission electron microscopy after trivalent antimony exposure. P-glycoprotein (P-gp) efflux pump activity was evaluated using the pump-specific inhibitor verapamil hydrochloride, and the role of thiol in trivalent antimony resistance was investigated using the enzymatic inhibitor L-buthionine sulfoximine. FINDINGS Antimony treatment induced fewer alterations in the cellular structure of L. infantum resistant isolates than in that of sensitive isolates. P-gp efflux activity was not involved in antimony resistance in these isolates. Importantly, the resistant isolates contained higher levels of thiol compared to the sensitive isolates, and inhibition of thiol synthesis in the resistant isolates recovered their sensitivity to trivalent antimony treatment, and enhanced the production of reactive oxygen species in promastigotes exposed to the drug. MAIN CONCLUSIONS Our results demonstrate that isolates from patients with antimony-refractory VL exhibited higher thiol levels than antimony-sensitive isolates. This indicates that redox metabolism plays an important role in the antimony-resistance of New World VL isolates.

Original languageEnglish (US)
Pages (from-to)119-125
Number of pages7
JournalMemorias do Instituto Oswaldo Cruz
Volume113
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

Bibliographical note

Funding Information:
doi: 10.1590/0074-02760170289 Financial support: CNPq, MCTI/CNPQ/Universal 14/2014 (460743/2014-7 TRM) and PROCAD/CASADINHO (552721/2011-5 RPA); FAPITEC/ SE/FUNTEC/CNPq No. 12/2009 (019.203.02712/2009-8 ARJ); CAPES; Programa Nacional de Incentivo à Pesquisa em Parasitologia Básica, Edital No. 032/2010 (ARJ); NIH (grant #SC2GM103741 - MWL); the Department of Defense (DOD) (grant #W911NF-14-1-0123 - MWL); and the National Science Foundation (NSF) (grant #1428768 - MWL). + Corresponding author: tmoura.ufs@gmail.com Received 19 July 2017 Accepted 6 October 2017

Funding Information:
Financial support: CNPq, MCTI/CNPQ/Universal 14/2014 (460743/2014-7 TRM) and PROCAD/CASADINHO (552721/2011-5 RPA); FAPITEC/ SE/FUNTEC/CNPq No. 12/2009 (019.203.02712/2009-8 ARJ); CAPES; Programa Nacional de Incentivo à Pesquisa em Parasitologia Básica, Edital No. 032/2010 (ARJ); NIH (grant #SC2GM103741 - MWL); the Department of Defense (DOD) (grant #W911NF-14-1-0123 - MWL); and the National Science Foundation (NSF) (grant #1428768 - MWL).To the Plataforma de Microscopia, teams from Laboratório Integrado de Microbiologia e Imunoregulação (LIMI), and Laboratório de Imunoparasitologia (LIP) from Instituto Gonçalo Moniz/Fiocruz-Bahia; and all colleagues from Laboratório de Biologia Molecular da UFS/Brazil.

Publisher Copyright:
© 2018, Fundacao Oswaldo Cruz. All rights reserved.

Keywords

  • Antimony
  • Drug resistance
  • Leishmania
  • Visceral leishmaniasis

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