Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes

Grennady Wirjanata, Irene Handayuni, Pak Prayoga, Leo Leonardo, Dwi Apriyanti, Leily Trianty, Ruland Wandosa, Basbak Gobay, Enny Kenangalem, Jeanne Rini Poespoprodjo, Rintis Noviyanti, Dennis E. Kyle, Qin Cheng, Ric N. Price, Jutta Marfurt

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
    Original languageEnglish
    Article numbere00355
    Pages (from-to)1-10
    Number of pages10
    JournalAntimicrobial Agents and Chemotherapy
    Volume61
    Issue number8
    Early online date22 May 2017
    DOIs
    Publication statusPublished - 25 Jul 2017

    Fingerprint

    Plasmodium vivax
    Chloroquine
    Plasmodium falciparum
    Phenotype
    L 703606
    Mibefradil
    Primaquine
    Verapamil
    Schizonts
    Indonesia

    Cite this

    Wirjanata, Grennady ; Handayuni, Irene ; Prayoga, Pak ; Leonardo, Leo ; Apriyanti, Dwi ; Trianty, Leily ; Wandosa, Ruland ; Gobay, Basbak ; Kenangalem, Enny ; Poespoprodjo, Jeanne Rini ; Noviyanti, Rintis ; Kyle, Dennis E. ; Cheng, Qin ; Price, Ric N. ; Marfurt, Jutta. / Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 8. pp. 1-10.
    @article{233ceb5942464d72b14e5b293be03404,
    title = "Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes",
    abstract = "High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50{\%} inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.",
    keywords = "Chloroquine, Chloroquine resistance reversal, Drug resistance, Malaria, Plasmodium falciparum, Plasmodium vivax",
    author = "Grennady Wirjanata and Irene Handayuni and Pak Prayoga and Leo Leonardo and Dwi Apriyanti and Leily Trianty and Ruland Wandosa and Basbak Gobay and Enny Kenangalem and Poespoprodjo, {Jeanne Rini} and Rintis Noviyanti and Kyle, {Dennis E.} and Qin Cheng and Price, {Ric N.} and Jutta Marfurt",
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    Wirjanata, G, Handayuni, I, Prayoga, P, Leonardo, L, Apriyanti, D, Trianty, L, Wandosa, R, Gobay, B, Kenangalem, E, Poespoprodjo, JR, Noviyanti, R, Kyle, DE, Cheng, Q, Price, RN & Marfurt, J 2017, 'Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes', Antimicrobial Agents and Chemotherapy, vol. 61, no. 8, e00355, pp. 1-10. https://doi.org/10.1128/AAC.00355-17

    Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes. / Wirjanata, Grennady; Handayuni, Irene; Prayoga, Pak; Leonardo, Leo; Apriyanti, Dwi; Trianty, Leily; Wandosa, Ruland; Gobay, Basbak; Kenangalem, Enny; Poespoprodjo, Jeanne Rini; Noviyanti, Rintis; Kyle, Dennis E.; Cheng, Qin; Price, Ric N.; Marfurt, Jutta.

    In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 8, e00355, 25.07.2017, p. 1-10.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes

    AU - Wirjanata, Grennady

    AU - Handayuni, Irene

    AU - Prayoga, Pak

    AU - Leonardo, Leo

    AU - Apriyanti, Dwi

    AU - Trianty, Leily

    AU - Wandosa, Ruland

    AU - Gobay, Basbak

    AU - Kenangalem, Enny

    AU - Poespoprodjo, Jeanne Rini

    AU - Noviyanti, Rintis

    AU - Kyle, Dennis E.

    AU - Cheng, Qin

    AU - Price, Ric N.

    AU - Marfurt, Jutta

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    N2 - High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

    AB - High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

    KW - Chloroquine

    KW - Chloroquine resistance reversal

    KW - Drug resistance

    KW - Malaria

    KW - Plasmodium falciparum

    KW - Plasmodium vivax

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