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Mechanisms of Resistance

In Vitro Activities of Quinine and Other Antimalarials and pfnhe Polymorphisms in Plasmodium Isolates from Kenya

John Okombo, Steven M. Kiara, Josea Rono, Leah Mwai, Lewa Pole, Eric Ohuma, Steffen Borrmann, Lynette Isabella Ochola, Alexis Nzila
John Okombo
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Steven M. Kiara
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Josea Rono
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Leah Mwai
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
2 University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
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Lewa Pole
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Eric Ohuma
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Steffen Borrmann
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
3Institute of Hygiene, University of Heidelberg School of Medicine, Heidelberg, Germany
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Lynette Isabella Ochola
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
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Alexis Nzila
1Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
2 University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
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  • For correspondence: anzila@kilifi.kemri-wellcome.org
DOI: 10.1128/AAC.00325-10
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  • FIG. 1.
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    FIG. 1.

    In vitro activities of the amino alcohols quinine (QN), mefloquine (MFQ), and halofantrine (HLF). Values on the y axis represent drug concentrations that inhibit 50% of parasite growth (IC50s), in nanomoles. Median IC50s for each drug are also represented.

  • FIG. 2.
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    FIG. 2.

    Diagram of pfnhe-1 gene (A) and ms4760 microsatellite sequence profiles (B). (A) Asterisks indicate polymorphic codons (894, 950, and 1437). (B) ms4760 profiles. Profiles 1 to 18 were previously described (10, 13), and we identified 4 new profiles, 20 to 23.

  • FIG. 3.
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    FIG. 3.

    Association between the number of DNNND repeats in pfnhe and the quinine concentration that inhibits 50% (A) or 90% (B) of parasite growth. Isolate numbers are in brackets. (A) Our current data from Kilifi. (B) Data from Ferdig et al. (10) (from Table 1). In both graphs, differences between 1 and 2 and between 2 and 3 repeats were significant (P < 0.0 5), while those between 1 and 3 repeats were not (P > 0.05). In the work of Fergid et al. (10), 1 isolate had 4 copies (IC90 = 582 nM) and was not included.

  • FIG. 4.
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    FIG. 4.

    Relationship between drug concentrations that inhibit 50% of parasite growth (IC50s) and the genotype combination of DNNND repeat number and pfmdr1-86 (A) or pfcrt-76 (B). On a backdrop of 2 repeats of DNNND, the pfcrt-76 genotype did not affect QN activity, while a 3-fold increase in the IC50 was observed for the pfmdr1-86 mutants.

Tables

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  • TABLE 1.

    IC50s of quinine and pfnhe polymorphisms in P. falciparum

    IsolateIC50 (nM)Codon polymorphismsMicrosatellite polymorphisms
    8949501437No. of SDNN repeatsmsR1ms3580ms4760
    3D727.1AATGTGTAT4AbsentNIHms4760-2
    AK127569.5AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-1
    AK182549.2AATGGGTTT2TCDNNMPNNNMSNNNNIHms4760-1
    AK227495.3AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-1
    CDA-1553333.3AATGGGTTT4TCDNNMPNNNMSNNNNIHms4760-1
    AK150 D-0296.6AATGGGTAT3AbsentNIHms4760-1
    AK249270.4AATGTGTAT3AbsentNIHms4760-1
    AK121270.2AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-21
    AK158234.0AATGGGTAT2TCDNNMPNNNMSNNNNIHms4760-1
    AK167227.0AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-1
    AK222210.5AATGGGTAT2TCDNNMPNNNMSNNNNIHms4760-1
    AK152 D-56207.7AAAGTGTAT2AbsentNIHms4760-6
    AK062181.5AATGTGTAT4TCDNNMPNNNMSNNNNIHms4760-1
    AK144145.8AATGTGTTT4AbsentNIHms4760-23
    AK018141.1AATGGGTTT2AbsentNIHms4760-20
    AK150 D-4291.6AATGGGTAT2AbsentNIHms4760-1
    906780.1AATGTGTAT4TCDNNMPNNNMSNNNNIHms4760-3
    888578.2AATGGGTAT3AbsentNIHms4760-22
    AK18373.9AATGGGTTT4TCDNNMPNNNMSNNNAbsentms4760-20
    681673.3AATGGGTAT1TCDNNMPNNNMSNNNNIHms4760-18
    896655.8AATGTGTAT4TCDNNMPNNNMSNNNAbsentms4760-1
    AK033 D-4954.1AATGGGTAT3TCDNNMPNNNMSNNNNIHms4760-7
    AK022D-042.4AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-22
    907041.5AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-22
    897735.9AATGGGTTT3AbsentNIHms4760-7
    AK033 D-032.8AATGGGTAT4AbsentNIHms4760-1
    896830.6AAAGGGTAT4AbsentNIHms4760-2
    894827.8AAAGGGTAT4AbsentNIHms4760-7
    AK022 D-2822.0AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-1
    897320.0AATGGGTAT4TCDNNMPNNNMSNNNNIHms4760-7
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In Vitro Activities of Quinine and Other Antimalarials and pfnhe Polymorphisms in Plasmodium Isolates from Kenya
John Okombo, Steven M. Kiara, Josea Rono, Leah Mwai, Lewa Pole, Eric Ohuma, Steffen Borrmann, Lynette Isabella Ochola, Alexis Nzila
Antimicrobial Agents and Chemotherapy Jul 2010, 54 (8) 3302-3307; DOI: 10.1128/AAC.00325-10

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In Vitro Activities of Quinine and Other Antimalarials and pfnhe Polymorphisms in Plasmodium Isolates from Kenya
John Okombo, Steven M. Kiara, Josea Rono, Leah Mwai, Lewa Pole, Eric Ohuma, Steffen Borrmann, Lynette Isabella Ochola, Alexis Nzila
Antimicrobial Agents and Chemotherapy Jul 2010, 54 (8) 3302-3307; DOI: 10.1128/AAC.00325-10
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    • ABSTRACT
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KEYWORDS

antimalarials
Plasmodium falciparum
Polymorphism, Genetic
Quinine
Sodium-Hydrogen Exchangers

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