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Antimony transport mechanisms in resistant leishmania parasites

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Abstract

Antimonial compounds have been used for more than a century in the treatment of the parasitic disease leishmaniasis. Although pentavalent antimonials are still first-line drugs in several developing countries, this class of drugs is no longer recommended in the Indian sub-continent because of the emergence of drug resistance. The precise mechanisms involved in the resistance of leishmania parasites to antimony are still subject to debate. It is now well documented that drug resistance in leishmania parasites is a multifactorial phenomenon involving multiple genes whose expression pattern synergistically leads to the resistance phenotype. The reduction of intracellular antimony accumulation is a frequent change observed in resistant leishmania cells; however, no comprehensive transport model has been presented so far to explain this change and its contribution to Leishmania resistance. The present review firstly covers the actual knowledge on the metabolism of antimonial drugs, the mechanisms of their transmembrane transport and intracellular processing in Leishmania. It further describes both the functional and molecular changes associated with Sb resistance in this organism. Possible transport models based on the actual knowledge are then presented, as well as their functional implications. Biophysical and pharmacological strategies are finally proposed for the precise identification of the transport pathways.

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Abbreviations

T(SH)2 :

trypanothione

GSH:

glutathione

AQP1:

aquaglyceroporin 1

MRPA:

multidrug resistance-associated protein A

MRP:

multidrug resistance-associated protein

MDR:

multidrug resistance

MAPK:

mitogen-activated protein kinase

TryR:

trypanothione reductase

ODC:

ornithine decarboxylase

γ-GCS:

γ-glutamylcysteine synthetase

HBTF :

terbinafine-associated encoding gene

PRT1:

pterine reductase

APX:

ascorbate-dependent peroxidase

G6PDH:

glucose-6-phosphate dehydrogenase

NT4:

nucleobase transporter

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Acknowledgments

We acknowledge the Brazilian agencies, “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (303046/2009 and studentship), “Fundação de Amparo à Pesquisa do Estado de Minas Gerais” (PPM-00382-11; REDE 40/11; CBB-APQ-01123-09) and “Coordenação de Aperfeiçoamento de Pessoal de Nível Superior” (2447/2009 and studentship) for financial support. R.M.N. is supported by a Government of Canada DFAIT post-doctoral research fellowship. F.F. is recipient of a research fellowship from CNPq. The authors declare that they have no conflict of interest.

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The authors declare that they have no conflict of Interest.

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  1. Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos 6627, Pampulha, 31270-901, Belo Horizonte, Minas Gerais, Brazil

    Frédéric Frézard & Priscila G. Reis

  2. Centre de Recherche en Infectiologie du Centre Hospitalier de l’Université Laval, 2705, Boulevard Laurier, RC-709, G1V 4G2, Québec, QC, Canada

    Rubens Monte-Neto

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  1. Frédéric Frézard
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  2. Rubens Monte-Neto
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  3. Priscila G. Reis
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Correspondence to Frédéric Frézard.

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Special Issue Advances in Biophysics in Latin America

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Frézard, F., Monte-Neto, R. & Reis, P.G. Antimony transport mechanisms in resistant leishmania parasites. Biophys Rev 6, 119–132 (2014). https://doi.org/10.1007/s12551-013-0134-y

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