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Molecular Pharmacology

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Research ArticleArticle

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Ibrahim A. Teka, Anne J. N. Kazibwe, Nasser El-Sabbagh, Mohammed I. Al-Salabi, Christopher P. Ward, Anthonius A. Eze, Jane C. Munday, Pascal Mäser, Enock Matovu, Michael P. Barrett and Harry P. de Koning
Molecular Pharmacology July 2011, 80 (1) 110-116; DOI: https://doi.org/10.1124/mol.111.071555
Ibrahim A. Teka
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Anne J. N. Kazibwe
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Nasser El-Sabbagh
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Mohammed I. Al-Salabi
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Christopher P. Ward
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Anthonius A. Eze
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Jane C. Munday
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Pascal Mäser
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Enock Matovu
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Michael P. Barrett
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Harry P. de Koning
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Abstract

African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(−/−), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidine-adapted line B48. The Km for diminazene transport in bloodstream tbat1(−/−) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(−/−), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Consortium for Parasitic Drug Development; a Commonwealth Scholarship; and the UK Medical Research Council [Grant 84733].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.071555.

  • ABBREVIATIONS:

    HAPT1
    high-affinity pentamidine transporter 1
    LAPT1
    low-affinity pentamidine transporter 1
    FCS
    fetal calf serum
    PPT
    procyclic pentamidine transporter
    PAO
    phenylarsine oxide
    AB
    assay buffer
    DB820
    6-(5-(4-amidinophenyl)furan-2-yl)nicotinamidine
    CPD0801
    2,5-bis(5-amidino-2-pyridyl)furan.

  • Received February 3, 2011.
  • Accepted March 24, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Ibrahim A. Teka, Anne J. N. Kazibwe, Nasser El-Sabbagh, Mohammed I. Al-Salabi, Christopher P. Ward, Anthonius A. Eze, Jane C. Munday, Pascal Mäser, Enock Matovu, Michael P. Barrett and Harry P. de Koning
Molecular Pharmacology July 1, 2011, 80 (1) 110-116; DOI: https://doi.org/10.1124/mol.111.071555

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Research ArticleArticle

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Ibrahim A. Teka, Anne J. N. Kazibwe, Nasser El-Sabbagh, Mohammed I. Al-Salabi, Christopher P. Ward, Anthonius A. Eze, Jane C. Munday, Pascal Mäser, Enock Matovu, Michael P. Barrett and Harry P. de Koning
Molecular Pharmacology July 1, 2011, 80 (1) 110-116; DOI: https://doi.org/10.1124/mol.111.071555
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