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ARTICLE

Mechanisms of Arsenical and Diamidine Uptake and Resistance in Trypanosoma brucei

Enock Matovu, Mhairi L. Stewart, Federico Geiser, Reto Brun, Pascal Mäser, Lynsey J. M. Wallace, Richard J. Burchmore, John C. K. Enyaru, Michael P. Barrett, Ronald Kaminsky, Thomas Seebeck, Harry P. de Koning
Enock Matovu
1Institute of Cell Biology, CH-3012 Bern
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Mhairi L. Stewart
2Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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Federico Geiser
1Institute of Cell Biology, CH-3012 Bern
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Reto Brun
3Swiss Tropical Institute, CH-4002 Basel
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Pascal Mäser
1Institute of Cell Biology, CH-3012 Bern
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Lynsey J. M. Wallace
2Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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Richard J. Burchmore
2Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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John C. K. Enyaru
4Livestock Health Research Institute, Tororo, Uganda
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Michael P. Barrett
2Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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Ronald Kaminsky
5Novartis Animal Health, CH-1566 St. Aubin, Switzerland
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Thomas Seebeck
1Institute of Cell Biology, CH-3012 Bern
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Harry P. de Koning
2Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom
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  • For correspondence: H.de-Koning@bio.gla.ac.uk
DOI: 10.1128/EC.2.5.1003-1008.2003
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    FIG. 1.

    Uptake of [3H]adenosine by the tbat1-null mutant. Uptake of 20 nM [3H]adenosine was inhibited by inosine (filled squares) with an IC50 of 1.1 ± 0.1 μM. Adenine failed to inhibit [3H]adenosine at concentrations as high as 100 μM when it was added alone (open squares). The inhibition induced by 1 mM adenine is attributable to a low-affinity inhibition of P1.

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    FIG. 2.

    Uptake of [3H]pentamidine by the tbat1-null mutant. The uptake of 15 nM [3H]pentamidine was unaffected by as much as 1 mM adenosine (filled circles) but was inhibited to a maximum of 64% by propamidine (open squares), with an IC50 of 6.5 μM. When increasing amounts of unlabeled pentamidine (filled squares) were added, [3H]pentamidine uptake was inhibited in a biphasic manner (P < 0.0001 by the F test), with the high-affinity component (IC50 = 25.1 nM) contributing 62% of total [3H] pentamidine transport. The IC50 of the low-affinity component was 19.5 μM for this experiment.

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    FIG. 3.

    In vitro sensitivities of bloodstream-form trypanosomes to arsenical trypanocides. (a) Wild-type T. b. brucei s427 parasites were incubated with or without 10 μM melarsen oxide in the presence of potential inhibitors. Traces: a, control (no arsenical); b, melarsen oxide only; c, melarsen oxide plus 4 mM adenosine; d, melarsen oxide plus 1 mM pentamidine; e, melarsen oxide plus 4 mM hypoxanthine. (b) Cells of the tbat1-null mutant were incubated with or without 10 μM cymelarsan. Traces: a, control (no arsenical); b, cymelarsan only; c, cymelarsan plus 0.1 μM pentamidine; d, cymelarsan plus 0.03 μM pentamidine; e, cymelarsan plus 0.01 μM pentamidine; f, cymelarsan plus 10 μM stilbamidine; g, cymelarsan plus 1 μM propamidine; h, cymelarsan plus 0.3 μM propamidine; i, cymelarsan plus 0.1 μM propamidine. (c) Cells of the tbat1-null mutant were incubated with or without 0.5 μM phenylarsine oxide. Traces: a, control (no arsenical); b, phenylarsine oxide only; c, phenylarsine oxide plus 10 mM adenosine; d, phenylarsine oxide plus 4 mM hypoxanthine; e, phenylarsine oxide plus 1 mM pentamidine; f, phenylarsine oxide plus 100 μM pentamidine; g, phenylarsine oxide plus 100 μM propamidine; h, phenylarsine oxide plus 100 μM stilbamidine. Arrow indicates time of phenylarsine oxide addition.

Tables

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  • TABLE 1.

    Drug resistance phenotype of the tbat1-null mutant compared to the parental wild-type strain

    DrugIC50a (ng/ml)Resistance factor
    Wild typeTbAT1−/− mutant
    Melarsoprol21 ± 349 ± 92.3
    Melarsen oxide3.7 ± 0.111 ± 0.13.0
    Cymelarsan6.1 ± 112 ± 32.0
    Pentamidine5.1 ± 212 ± 32.4
    Diminazene120 ± 302,300 ± 50019
    Propamidine67 ± 7750 ± 2011
    Stilbamidine680 ± 705,000 ± 1,3007.4
    • ↵ a IC50 were determined in vitro by using the Alamar Blue assay. Values are means from at least three independent experiments ± standard errors.

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Mechanisms of Arsenical and Diamidine Uptake and Resistance in Trypanosoma brucei
Enock Matovu, Mhairi L. Stewart, Federico Geiser, Reto Brun, Pascal Mäser, Lynsey J. M. Wallace, Richard J. Burchmore, John C. K. Enyaru, Michael P. Barrett, Ronald Kaminsky, Thomas Seebeck, Harry P. de Koning
Eukaryotic Cell Oct 2003, 2 (5) 1003-1008; DOI: 10.1128/EC.2.5.1003-1008.2003

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Mechanisms of Arsenical and Diamidine Uptake and Resistance in Trypanosoma brucei
Enock Matovu, Mhairi L. Stewart, Federico Geiser, Reto Brun, Pascal Mäser, Lynsey J. M. Wallace, Richard J. Burchmore, John C. K. Enyaru, Michael P. Barrett, Ronald Kaminsky, Thomas Seebeck, Harry P. de Koning
Eukaryotic Cell Oct 2003, 2 (5) 1003-1008; DOI: 10.1128/EC.2.5.1003-1008.2003
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KEYWORDS

Arsenicals
Nucleoside Transport Proteins
Pentamidine
Trypanosoma brucei brucei

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