The F423Y Mutation in the
            <i>pfmdr2</i>
            Gene and Mutations N51I, C59R, and S108N in the
            <i>pfdhfr</i>
            Gene Are Independently Associated with Pyrimethamine Resistance in Plasmodium falciparum Isolates

Briolant, Sébastien; Bogreau, Hervé; Gil, Marine; Bouchiba, Housem; Baret, Eric; Amalvict, Rémy; Rogier, Christophe; Pradines, Bruno

doi:10.1128/aac.05618-11

Cited by 21 publications

(15 citation statements)

References 20 publications

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“…Two other background markers affect transporter genes localized in the digestive vacuole of the parasite, the multidrug resistance transporter 2 and chloroquine resistance transporter 22,23 . The role of mdr2 in antimalarial drug resistance remains unclear, but it has been implicated in resistance to antifolates 24,25 and tolerance to heavy metals 26 . In crt , there are two closely linked background markers, both nonsynonymous variants affecting the same part of the membrane-spanning structure, some distance from the p.Lys76Thr variant that is the major determinant of chloroquine resistance 27 .…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of artemisinin-resistant Plasmodium falciparum

Miotto¹,

Amato²,

Ashley³

et al. 2015

Nat Genet

549

742

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We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population.

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Section: Discussionmentioning

confidence: 99%

Genetic architecture of artemisinin-resistant Plasmodium falciparum

Miotto¹,

Amato²,

Ashley³

et al. 2015

Nat Genet

549

742

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“…Hence, Pfmdr1 polymorphisms have been shown to reduce drug accumulation resulting in antimalarial resistance (Reed et al, 2000). Furthermore, a single nucleotide polymorphism (SNP) in Pfmdr2 (PF3D7_1447900), a heavy metal transporter (Rosenberg et al, 2006), is associated with in vitro resistance to pyrimethamine (Briolant et al, 2012). Recently, another SNP in Pfmdr2 showed a statistically significant association (p 5 2 3 10 210 ) with artemisinin resistance (Miotto et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Vital and dispensable roles of Plasmodium multidrug resistance transporters during blood‐ and mosquito‐stage development

Rijpma

Velden

Annoura

et al. 2016

Molecular Microbiology

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Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of malaria parasites. Four P. berghei genes (encoding MDR1, 4, 6 and 7) were refractory to deletion, indicating a vital role during blood stage multiplication and validating them as potential targets for antimalarial drugs. Mutants lacking expression of MDR2, MDR3 and MDR5 were generated in both P. berghei and P. falciparum, indicating a dispensable role for blood stage development. Whereas P. berghei mutants lacking MDR3 and MDR5 had a reduced blood stage multiplication in vivo, blood stage growth of P. falciparum mutants in vitro was not significantly different. Oocyst maturation and sporozoite formation in Plasmodium mutants lacking MDR2 or MDR5 was reduced. Sporozoites of these P. berghei mutants were capable of infecting mice and life cycle completion, indicating the absence of vital roles during liver stage development. Our results demonstrate vital and dispensable roles of MDR proteins during blood stages and an important function in sporogony for MDR2 and MDR5 in both Plasmodium species.

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“…Furthermore, amplification of and polymorphisms in the P. falciparum mdr1 and mrp1 genes have been associated with, e.g., artemisinin, chloroquine, lumefantrine, mefloquine, and quinine resistance [ 13 - 18 ]. In addition, polymorphisms and differential Asn-repeat lengths found in Pfmdr6 were shown to alter drug sensitivity to artesunate and piperaquine [ 19 - 22 ], while a single mutation in the heavy metal transporting Pf MDR2 [ 23 ] was linked to in vitro pyrimethamine resistance, which however, depended on dhfr mutation status [ 24 ]. These findings show an important role for ABC transport proteins in P. falciparum drug resistance acquisition.…”

Section: Introductionmentioning

confidence: 99%

PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs

Velden

Rijpma

Rüssel

et al. 2015

Malar J

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BackgroundMembrane-associated ATP binding cassette (ABC) transport proteins hydrolyze ATP in order to translocate a broad spectrum of substrates, from single ions to macromolecules across membranes. In humans, members from this transport family have been linked to drug resistance phenotypes, e.g., tumour resistance by enhanced export of chemotherapeutic agents from cancer cells due to gene amplifications or polymorphisms in multidrug resistance (MDR) protein 1. Similar mechanisms have linked the Plasmodium falciparum PfMDR1 transporter to anti-malarial drug resistance acquisition. In this study, the possible involvement of two related MDR proteins, PfMDR2 and PfMDR5, to emerging drug resistance is investigated by a reverse genetics approach.MethodsA homologous double crossover strategy was used to generate P. falciparum parasites lacking the Pfmdr2 (PfΔmdr2) or Pfmdr5 (PfΔmdr5) gene. Plasmodium lactate dehydrogenase activity was used as read-out for sensitivity to artemisinin (ART), atovaquone (ATO), dihydroartemisinin (DHA), chloroquine (CQ), lumefantrine (LUM), mefloquine (MQ), and quinine (QN). Differences in half maximal inhibitory concentration (IC50) values between wild type and each mutant line were determined using a paired t-test.ResultsBoth PfΔmdr2 and PfΔmdr5 clones were capable of asexual multiplication. Upon drug exposure, PfΔmdr2 showed a marginally decreased sensitivity to ATO (IC50 of 1.2 nM to 1.8 nM), MQ (124 nM to 185 nM) and QN (40 nM to 70 nM), as compared to wild type (NF54) parasites. On the other hand, PfΔmdr5 showed slightly increased sensitivity to ART (IC50 of 26 nM to 19 nM).ConclusionBoth Pfmdr2 and Pfmdr5 are dispensable for blood stage development while the deletion lines show altered sensitivity profiles to commonly used anti-malarial drugs. The findings show for the first time that next to PfMDR2, the PfMDR5 transport protein could play a role in emerging drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0581-y) contains supplementary material, which is available to authorized users.

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The F423Y Mutation in the pfmdr2 Gene and Mutations N51I, C59R, and S108N in the pfdhfr Gene Are Independently Associated with Pyrimethamine Resistance in Plasmodium falciparum Isolates

Cited by 21 publications

References 20 publications

Genetic architecture of artemisinin-resistant Plasmodium falciparum

Genetic architecture of artemisinin-resistant Plasmodium falciparum

Vital and dispensable roles of Plasmodium multidrug resistance transporters during blood‐ and mosquito‐stage development

PfMDR2 and PfMDR5 are dispensable for Plasmodium falciparum asexual parasite multiplication but change in vitro susceptibility to anti-malarial drugs

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