Affinage · Plasmodium

MDR1

PF3D7_0523000 · multidrug resistance protein 1

Annotated
2026-09-07
94 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDR1 (PF3D7_0523000, historically called Pgh1) is an ATP-binding cassette transporter of the P. falciparum digestive (food) vacuole membrane that acts as a solute/drug importer and is a central determinant of parasite susceptibility to structurally unrelated antimalarials (PMID:1674943, PMID:16794577, PMID:18713316). It is expressed throughout the asexual erythrocytic cycle and localizes to the digestive vacuole membrane (PMID:1674943). Functional expression in Xenopus oocytes established that MDR1 transports vinblastine, chloroquine, quinine, and halofantrine, and that its coding polymorphisms reshape substrate specificity — wild-type protein transports quinine and chloroquine but not halofantrine, while polymorphic variants show the reciprocal preference (PMID:18713316); a food-vacuole solute-import phenotype was independently linked to specific Pgh1 variants by positional cloning (PMID:16794577). Direct genetic manipulation — allelic exchange, zinc-finger nuclease and CRISPR-Cas9 editing — demonstrated that point mutations (N86Y, Y184F, S1034C, N1042D, D1246Y) confer or modulate resistance to mefloquine, quinine, halofantrine, chloroquine, amodiaquine, lumefantrine, and artemisinin in a strain- and haplotype-specific, often reciprocal manner (PMID:10706290, PMID:16091034, PMID:27189525, PMID:27073104). Independently, gene amplification and overexpression of MDR1, without coding mutations, is the primary mechanism of mefloquine resistance and reduced artemisinin-derivative sensitivity, and reciprocally lowers chloroquine resistance (PMID:1353446, PMID:8302844, PMID:15288742, PMID:20350946); these resistance-associated changes carry a measurable intraerythrocytic fitness cost in the absence of drug pressure (PMID:15686571). A cryo-EM structure of MDR1 bound to ACT-451840 shows the inhibitor lodged in the central cavity locking the transporter inward-open and suppressing its basal ATPase activity, providing the molecular basis for cross-modulation between ACT-451840 and mefloquine susceptibility (PMID:42203772).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1989 Medium

    The question of whether P. falciparum possesses mammalian-type multidrug resistance machinery was answered by identifying mdr-related genes, one of which (MDR1) was elevated in copy number and expression in a multidrug-resistant strain.

    Evidence Southern and Northern blotting comparing resistant and sensitive strains

    PMID:2658061

    Open questions at the time
    • Correlation only, no functional or causal test
    • Does not establish transport activity or substrates
  2. 1991 High

    Establishing where MDR1 acts, immunolocalization placed the ~160 kDa Pgh1 protein on the digestive vacuole membrane, and equal expression in resistant and sensitive isolates showed overexpression is not required for chloroquine resistance.

    Evidence Immunoblotting and immunoelectron/immunofluorescence microscopy across isolates

    PMID:1674943

    Open questions at the time
    • Transport directionality and substrates not defined
    • Localization does not explain mechanism of resistance
  3. 1991 High

    The structural mechanism of MDR1 amplification was resolved as recurrent, independent head-to-tail tandem duplication with A/T-tract breakpoints.

    Evidence YAC cloning, inverted PCR breakpoint sequencing, macrorestriction mapping across isolates

    PMID:1922044

    Open questions at the time
    • Does not link amplification to a specific drug phenotype
    • Regulation of copy number selection not addressed
  4. 1994 High

    Causality of copy number was demonstrated bidirectionally: mefloquine selection drove MDR1 amplification/overexpression with cross-resistance to halofantrine and quinine and reciprocal loss of chloroquine resistance, while chloroquine selection deamplified the gene.

    Evidence In vitro drug selection with Southern/Northern/Western analysis and chromosome mapping

    PMID:1353446 PMID:7985758 PMID:8302844

    Open questions at the time
    • Correlation between copy number and phenotype at the population level, molecular transport mechanism not yet shown
    • Contribution of co-selected point mutations vs amplification not fully separable in selection lines
  5. 2000 High

    The role of coding mutations was proven causally: allelic exchange showed specific MDR1 mutations confer mefloquine, quinine and halofantrine resistance and modulate artemisinin/chloroquine sensitivity, and a genetic cross confirmed allelic association with mefloquine and artemisinin susceptibility.

    Evidence Allelic-exchange transfection and HB3x3D7 genetic cross with in vitro IC50 assays

    PMID:10706290 PMID:10844681

    Open questions at the time
    • Strain-specific effects indicate genetic-background dependence not fully mapped
    • Mechanism by which mutations change drug handling not defined biochemically
  6. 2005 High

    The evolutionary constraint on resistance was quantified: chloroquine-resistance-associated 1034/1042/1246 mutations impose ~25% intraerythrocytic fitness cost partly via reduced merozoite viability.

    Evidence Isogenic allelic-exchange lines in competitive growth assays

    PMID:15686571

    Open questions at the time
    • Molecular basis of the fitness cost not resolved
    • Cost of amplification vs point mutations not separated
  7. 2006 High

    The dose-dependence of MDR1 expression on drug response was shown by disrupting one copy in a resistant line, lowering expression and reducing mefloquine, lumefantrine, halofantrine, quinine and artemisinin resistance without affecting chloroquine; a Fluo-4 assay linked variant Pgh1 to food-vacuole solute import.

    Evidence Allelic-exchange copy-number reduction, RT-PCR/Western, drug assays; subcellular Fluo-4 phenotype with positional cloning

    PMID:16794577 PMID:16845638

    Open questions at the time
    • Directionality of transport (import vs efflux) inferred, not directly measured here
    • Identity of physiological solute substrates undefined
  8. 2006 Medium

    Species divergence was established: in P. chabaudi, stable artemisinin/artesunate resistance arose without mdr1 mutation or amplification, showing MDR1 is not the artemisinin-resistance mechanism in this rodent model.

    Evidence In vitro selection with full-length sequencing and copy-number qPCR

    PMID:16436700

    Open questions at the time
    • Negative result; does not identify the responsible locus
    • Species-specific, not directly transferable to P. falciparum
  9. 2008 High

    Direct transport function and variant-dependent substrate selectivity were established biochemically: heterologously expressed MDR1 imported vinblastine, chloroquine, quinine and halofantrine, with polymorphic variants showing reciprocal quinine/chloroquine versus halofantrine handling and quinine acting as an inhibitor.

    Evidence Heterologous expression in Xenopus oocytes with transport and substrate-specificity assays

    PMID:18713316

    Open questions at the time
    • Oocyte system may not reproduce native vacuolar electrochemical context
    • Kinetics and stoichiometry of transport not fully defined
  10. 2016 High

    Precision editing dissected individual codon contributions, showing N86Y and Y184F reciprocally modulate ACT partner-drug susceptibility in a haplotype-specific manner and that MDR1 point mutations mediate resistance to novel compounds while sensitizing to other antimalarials.

    Evidence ZFN and CRISPR-Cas9 editing of codons 86/184 with multi-drug IC50 assays in defined backgrounds and gametocytes

    PMID:27073104 PMID:27189525

    Open questions at the time
    • Interplay with PfCRT background only partially characterized
    • Structural basis of altered substrate handling not yet resolved at this stage
  11. 2026 High

    The structural and enzymatic mechanism of inhibition was resolved: cryo-EM of ACT-451840-bound MDR1 shows the inhibitor in the central cavity locking an inward-open conformation and suppressing basal ATPase activity, explaining cross-modulation with mefloquine and selectivity over human ABCB1.

    Evidence 3.42 Å cryo-EM structure with ATPase biochemical assay and comparative structural analysis

    PMID:42203772

    Open questions at the time
    • Structures of drug-transporting (outward) states not captured
    • Structural basis of copy-number-driven resistance not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the transport cycle, substrate binding, and native physiological cargo of MDR1 quantitatively integrate to determine directional drug movement across the digestive vacuole membrane remains incompletely defined.
  • Native endogenous substrate(s) not identified
  • Transport directionality and kinetics in the parasite not directly measured
  • Full conformational cycle beyond inward-open inhibited state not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification
No controlled-vocabulary terms were assigned to this entry.

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 PfMDR1 (Pgh1) is a ~160 kDa protein expressed throughout the asexual erythrocytic life cycle and localizes to the membrane of the digestive vacuole of mature P. falciparum parasites, as demonstrated by immunofluorescence and immunoelectron microscopy. Quantitative immunoblotting showed approximately equal expression in chloroquine-resistant and sensitive isolates, indicating that overexpression is not essential for chloroquine resistance. Immunoblotting, immunofluorescence microscopy, immunoelectron microscopy The Journal of cell biology High 1674943
1989 P. falciparum contains at least two genes related to mammalian multidrug resistance (mdr) genes; at least one (PfMDR1) is expressed at higher levels and present in higher copy number in a multidrug-resistant strain compared to a sensitive strain. Southern blotting (copy number), Northern blotting / expression analysis Science (New York, N.Y.) Medium 2658061
1991 Amplification of pfmdr1 in P. falciparum arises as multiple independent events; the five copies in isolate B8 are arranged in head-to-tail tandem configuration with A/T tract breakpoints, revealing the mechanism of tandem amplification. Yeast artificial chromosome cloning, inverted PCR sequencing of amplicon breakpoints, macrorestriction mapping Molecular and cellular biology High 1922044
1992 Selection of P. falciparum for high-level chloroquine resistance results in de-amplification (loss) of the pfmdr1 gene amplification and loss of Pgh1 over-production, demonstrating that pfmdr1 overexpression is incompatible with high-level chloroquine resistance. Conversely, deamplification was accompanied by increased sensitivity to mefloquine, establishing a direct linkage between pfmdr1 copy number and reciprocal chloroquine vs. mefloquine resistance. Drug selection in vitro, Southern blotting (copy number), immunoblotting (protein expression), verapamil reversal assay The EMBO journal High 1353446
1994 In vitro mefloquine selection of P. falciparum directly causes amplification and overexpression of pfmdr1 and its protein Pgh1, conferring cross-resistance to halofantrine and quinine while inversely reducing chloroquine resistance. This demonstrates that pfmdr1 amplification/overexpression is causally linked to a true multidrug-resistance phenotype. In vitro drug selection, Southern blotting (copy number and chromosome size), Northern and Western blotting (expression), macrorestriction mapping Proceedings of the National Academy of Sciences of the United States of America High 8302844
2000 Allelic exchange (transfection-based genetic modification) of pfmdr1 demonstrated that specific mutations in Pgh1 directly confer resistance to mefloquine, quinine, and halofantrine, and modulate sensitivity to artemisinin and chloroquine in a strain-specific manner, providing direct causal proof of pfmdr1's role in multidrug resistance. Allelic exchange transfection, in vitro drug susceptibility assays (IC50) Nature High 10706290
2000 In a genetic cross between P. falciparum strains HB3 and 3D7, complete allelic association was found between the HB3-like pfmdr1 allele and increased sensitivity to mefloquine and artemisinin in progeny, establishing pfmdr1 as a determinant of susceptibility to these structurally unrelated antimalarials. Genetic cross, progeny genotyping, in vitro drug susceptibility assays Molecular microbiology High 10844681
2004 Increased copy number of pfmdr1 (determined by real-time PCR) is the primary determinant of in vitro and in vivo mefloquine resistance and reduced artesunate sensitivity in P. falciparum from the Thailand-Burma border, with pfmdr1 copy number amplification associated with a hazard ratio of 6.3 for mefloquine monotherapy treatment failure. Real-time PCR (copy number quantification), in vitro IC50, Cox regression of clinical outcomes Lancet (London, England) High 15288742
2005 Allelic exchange of pfmdr1 3' coding region point mutations in P. falciparum GC03 and 3BA6 lines showed that the N1042D mutation contributes to quinine and quinidine resistance, and the triple mutation S1034C/N1042D/D1246Y (prevalent in South America) enhances susceptibility to mefloquine, halofantrine, and artemisinin. Minimal effect on chloroquine resistance was observed in these lines. Allelic exchange transfection, in vitro drug susceptibility assays (IC50) Molecular microbiology High 16091034
2006 Genetic disruption of one of two pfmdr1 copies in the drug-resistant FCB line reduced pfmdr1 mRNA and protein expression and decreased mefloquine IC50 ~3-fold, also increasing susceptibility to lumefantrine, halofantrine, quinine, and artemisinin, but not chloroquine. This directly demonstrated that pfmdr1 copy number/expression level causally determines susceptibility to multiple antimalarials. Genetic disruption (allelic exchange to reduce copy number), RT-PCR, Western blot, in vitro drug susceptibility assays The Journal of infectious diseases High 16845638
2006 A surrogate functional assay using subcellular distribution of Fluo-4 acetoxymethylester identified that Pgh1/PfMDR1 variants associated with altered drug responses preferentially import solutes (including certain antimalarial drugs) into the food vacuole. Genetic and positional cloning causatively linked the food vacuolar Fluo-4 staining phenotype to specific Pgh1 variants, supporting a model where PfMDR1 acts as a food vacuole importer. Fluorescence microscopy (Fluo-4 subcellular staining phenotype), genetic mapping/positional cloning, pharmacological assays The EMBO journal High 16794577
2008 PfMDR1 was functionally expressed in Xenopus laevis oocytes and shown to transport vinblastine (an established mammalian MDR1 substrate), halofantrine, quinine, and chloroquine. Polymorphisms in Pgh1 alter substrate specificity: wild-type Pgh1 transports quinine and chloroquine but not halofantrine, whereas polymorphic variants transport halofantrine but not quinine and chloroquine. Quinine also acts as an inhibitor of Pgh1. This supports the model that PfMDR1 mediates import of drugs into the food vacuole in a variant-specific manner. Heterologous expression in Xenopus laevis oocytes, transport assays, substrate specificity analysis Molecular microbiology High 18713316
2010 In vitro selection of P. falciparum lines W2 and TM91C235 for resistance to artelinic acid resulted in decreased susceptibility to artemisinin, mefloquine, quinine, halofantrine, and lumefantrine. This was accompanied by increased pfmdr1 copy number, mRNA expression, and protein expression, without any mutations in the coding sequences of pfmdr1, pfcrt, pfatp6, pftctp, or pfubcth, demonstrating that pfmdr1 amplification alone (without coding mutations) is a mechanism for artemisinin derivative resistance. In vitro drug selection, real-time PCR (copy number), RT-PCR (mRNA expression), Western blot (protein), gene sequencing Antimicrobial agents and chemotherapy High 20350946
2016 Zinc-finger nuclease (ZFN)-mediated genetic modification of PfMDR1 at amino acids 86 and 184 in P. falciparum demonstrated that the N86Y mutation augments resistance to amodiaquine and chloroquine while increasing susceptibility to lumefantrine, mefloquine, and dihydroartemisinin. The N86 plus Y184F isoform moderately reduces piperaquine potency in strains with an Asian/African PfCRT variant, confirming that PfMDR1 mutations modulate ACT partner drug susceptibility in a haplotype-specific manner. Zinc-finger nuclease gene editing, in vitro drug susceptibility assays (IC50), genetic background analysis Nature communications High 27189525
2016 CRISPR-Cas9 gene editing confirmed that specific PfMDR1 point mutations mediate resistance to the piperazine-containing compound ACT-451840 in P. falciparum asexual blood stages and stage V gametocytes, while simultaneously increasing susceptibility to lumefantrine, mefloquine, quinine, and amodiaquine. PfMDR1 resides on the digestive vacuole membrane and acts as an ABC transporter whose substrate specificity is altered by point mutations. CRISPR-Cas9 gene editing, in vitro drug susceptibility assays, gametocyte stage assays Molecular microbiology High 27073104
2005 Competition experiments between P. falciparum strains carrying wild-type versus pfmdr1 codons 1034/1042/1246 mutations (introduced by allelic exchange) showed that chloroquine-resistance-associated pfmdr1 mutations confer a ~25% fitness cost during intraerythrocytic asexual growth in the absence of drug pressure, with at least part attributable to diminished merozoite viability. Allelic exchange, competitive growth assays, parasite fitness quantification Molecular microbiology High 15686571
2026 Cryo-electron microscopy structure of PfMDR1 in complex with ACT-451840 was determined at 3.42 Å resolution. The structure reveals that ACT-451840 binds within the central cavity and locks PfMDR1 in an inward-open conformation, inhibiting its basal ATPase activity. Structural comparison with the mefloquine-bound state provides a molecular explanation for how ACT-451840 resistance mutations sensitize the transporter to mefloquine. Comparative structural analysis and biochemical characterization with human ABCB1 revealed the selective mechanism of ACT-451840 against PfMDR1. Cryo-electron microscopy (3.42 Å), ATPase activity biochemical assay, structural comparison Nature communications High 42203772
2006 In P. chabaudi, genetically stable artemisinin and artesunate-resistant lines were selected in vitro (showing 15-fold and 6-fold resistance, respectively). Sequencing of mdr1, cg10, tctp, and atp6 showed no mutations in these genes and no changes in copy number, demonstrating that mdr1 mutations and amplification are NOT the mechanism of artemisinin resistance in this rodent malaria model. In vitro drug selection, DNA sequencing (full-length), real-time PCR (copy number) Antimicrobial agents and chemotherapy Medium 16436700
1994 Stepwise in vitro mefloquine selection in P. falciparum produced a line with increased mefloquine, halofantrine, and quinine resistance together with amplification and overexpression of pfmdr1. A Y86F point mutation in pfmdr1 was amplified in increasingly resistant lines. Conversely, chloroquine-selected lines showed loss of pfmdr1 amplification, reversion of the mefloquine-resistance phenotype, and selection of the Y86 mutation previously associated with chloroquine resistance. In vitro drug selection, Southern blotting (copy number/amplification), Northern blotting (expression), sequencing The American journal of tropical medicine and hygiene Medium 7985758

Source papers

Stage 0 corpus · 94 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum. Nature 707 10706290
2004 Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet (London, England) 672 15288742
1989 Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science (New York, N.Y.) 408 2658061
2006 Decreasing pfmdr1 copy number in plasmodium falciparum malaria heightens susceptibility to mefloquine, lumefantrine, halofantrine, quinine, and artemisinin. The Journal of infectious diseases 322 16845638
1994 Selection for mefloquine resistance in Plasmodium falciparum is linked to amplification of the pfmdr1 gene and cross-resistance to halofantrine and quinine. Proceedings of the National Academy of Sciences of the United States of America 314 8302844
2016 Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. The Lancet. Infectious diseases 306 27818095
2016 A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype-genotype association study. The Lancet. Infectious diseases 306 27818097
2005 In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem). The Journal of infectious diseases 300 15717281
2005 pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum. Molecular microbiology 292 16091034
1991 A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole. The Journal of cell biology 255 1674943
2016 Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies. Nature communications 251 27189525
2000 The tyrosine-86 allele of the pfmdr1 gene of Plasmodium falciparum is associated with increased sensitivity to the anti-malarials mefloquine and artemisinin. Molecular and biochemical parasitology 234 10802315
2005 Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta tropica 229 15876420
2001 High-level chloroquine resistance in Sudanese isolates of Plasmodium falciparum is associated with mutations in the chloroquine resistance transporter gene pfcrt and the multidrug resistance Gene pfmdr1. The Journal of infectious diseases 208 11319692
2006 Amodiaquine and artemether-lumefantrine select distinct alleles of the Plasmodium falciparum mdr1 gene in Tanzanian children treated for uncomplicated malaria. Antimicrobial agents and chemotherapy 206 17194834
2009 A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria. Malaria journal 199 19413906
2007 Chloroquine resistant Plasmodium vivax: in vitro characterisation and association with molecular polymorphisms. PloS one 176 17971853
2021 Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda. The Journal of infectious diseases 167 33146722
1992 Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum. The EMBO journal 163 1353446
2006 Malaria parasites can develop stable resistance to artemisinin but lack mutations in candidate genes atp6 (encoding the sarcoplasmic and endoplasmic reticulum Ca2+ ATPase), tctp, mdr1, and cg10. Antimicrobial agents and chemotherapy 145 16436700
2006 Transporters involved in resistance to antimalarial drugs. Trends in pharmacological sciences 144 16996622
2000 Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of Plasmodium falciparum. Molecular microbiology 143 10844681
2009 In vitro activities of piperaquine, lumefantrine, and dihydroartemisinin in Kenyan Plasmodium falciparum isolates and polymorphisms in pfcrt and pfmdr1. Antimicrobial agents and chemotherapy 139 19770282
2005 Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 137 16271310
2009 Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia. Malaria journal 133 19138391
1994 A strong association between mefloquine and halofantrine resistance and amplification, overexpression, and mutation in the P-glycoprotein gene homolog (pfmdr) of Plasmodium falciparum in vitro. The American journal of tropical medicine and hygiene 132 7985758
2007 The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Tropical medicine & international health : TM & IH 131 17550470
2006 Recurrent gene amplification and soft selective sweeps during evolution of multidrug resistance in malaria parasites. Molecular biology and evolution 125 17124182
1995 Analysis of pfmdr1 and drug susceptibility in fresh isolates of Plasmodium falciparum from subsaharan Africa. Molecular and biochemical parasitology 119 8719157
2006 Genetic linkage of pfmdr1 with food vacuolar solute import in Plasmodium falciparum. The EMBO journal 117 16794577
2008 Amplification of pvmdr1 associated with multidrug-resistant Plasmodium vivax. The Journal of infectious diseases 114 18808339
2012 Plasmodium falciparum drug resistance phenotype as assessed by patient antimalarial drug levels and its association with pfmdr1 polymorphisms. The Journal of infectious diseases 111 23225895
2014 Directional selection at the pfmdr1, pfcrt, pfubp1, and pfap2mu loci of Plasmodium falciparum in Kenyan children treated with ACT. The Journal of infectious diseases 110 24994911
2008 Selection of Plasmodium falciparum multidrug resistance gene 1 alleles in asexual stages and gametocytes by artemether-lumefantrine in Nigerian children with uncomplicated falciparum malaria. Antimicrobial agents and chemotherapy 97 19075074
2010 Exploring the contribution of candidate genes to artemisinin resistance in Plasmodium falciparum. Antimicrobial agents and chemotherapy 96 20421395
2004 Identification of the Plasmodium vivax mdr-like gene (pvmdr1) and analysis of single-nucleotide polymorphisms among isolates from different areas of endemicity. The Journal of infectious diseases 96 15609238
2008 Plasmodium vivax resistance to chloroquine in Madagascar: clinical efficacy and polymorphisms in pvmdr1 and pvcrt-o genes. Antimicrobial agents and chemotherapy 91 18809933
2020 Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea. PLoS pathogens 89 33320907
1991 Amplification of the multidrug resistance gene pfmdr1 in Plasmodium falciparum has arisen as multiple independent events. Molecular and cellular biology 89 1922044
2022 Plasmodium falciparum resistance to artemisinin-based combination therapies. Current opinion in microbiology 86 36007459
2011 Novel polymorphisms in Plasmodium falciparum ABC transporter genes are associated with major ACT antimalarial drug resistance. PloS one 86 21633513
2010 Role of pfmdr1 amplification and expression in induction of resistance to artemisinin derivatives in Plasmodium falciparum. Antimicrobial agents and chemotherapy 85 20350946
2007 Seasonal carriage of pfcrt and pfmdr1 alleles in Gambian Plasmodium falciparum imply reduced fitness of chloroquine-resistant parasites. The Journal of infectious diseases 85 18008244
2013 The role of Pfmdr1 and Pfcrt in changing chloroquine, amodiaquine, mefloquine and lumefantrine susceptibility in western-Kenya P. falciparum samples during 2008-2011. PloS one 83 23675533
2021 Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook. International journal for parasitology. Drugs and drug resistance 81 34090067
2014 Molecular evidence of Plasmodium vivax mono and mixed malaria parasite infections in Duffy-negative native Cameroonians. PloS one 78 25084090
2010 The ABCs of multidrug resistance in malaria. Trends in parasitology 78 20541973
2005 pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Molecular microbiology 76 15686571
2008 Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Molecular microbiology 75 18713316
2008 Gene amplification of the multidrug resistance 1 gene of Plasmodium vivax isolates from Thailand, Laos, and Myanmar. Antimicrobial agents and chemotherapy 73 18443118
2018 Next-Generation Sequencing and Bioinformatics Protocol for Malaria Drug Resistance Marker Surveillance. Antimicrobial agents and chemotherapy 72 29439965
2011 Prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemether-lumefantrine in Uganda. The Journal of infectious diseases 72 21881128
2014 Role of Pfmdr1 in in vitro Plasmodium falciparum susceptibility to chloroquine, quinine, monodesethylamodiaquine, mefloquine, lumefantrine, and dihydroartemisinin. Antimicrobial agents and chemotherapy 70 25199781
2013 Plasmodium vivax chloroquine resistance and anemia in the western Brazilian Amazon. Antimicrobial agents and chemotherapy 70 24165179
2021 Drug susceptibility of Plasmodium falciparum in eastern Uganda: a longitudinal phenotypic and genotypic study. The Lancet. Microbe 69 34553183
2005 Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains. Experimental parasitology 69 15755424
2002 In vitro chloroquine susceptibility and PCR analysis of pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from Senegal. The American journal of tropical medicine and hygiene 67 12201579
2011 Increased pfmdr1 copy number and sequence polymorphisms in Plasmodium falciparum isolates from Sudanese malaria patients treated with artemether-lumefantrine. Antimicrobial agents and chemotherapy 66 21896916
2014 Return of chloroquine-sensitive Plasmodium falciparum parasites and emergence of chloroquine-resistant Plasmodium vivax in Ethiopia. Malaria journal 64 24964730
2008 Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1. The Journal of infectious diseases 64 18582193
2007 Resistance-mediating Plasmodium falciparum pfcrt and pfmdr1 alleles after treatment with artesunate-amodiaquine in Uganda. Antimicrobial agents and chemotherapy 64 17562798
2017 Transmission dynamics of co-endemic Plasmodium vivax and P. falciparum in Ethiopia and prevalence of antimalarial resistant genotypes. PLoS neglected tropical diseases 62 28746333
2015 Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance. Antimicrobial agents and chemotherapy 61 26014942
2009 Analysis of single-nucleotide polymorphisms in the crt-o and mdr1 genes of Plasmodium vivax among chloroquine-resistant isolates from the Brazilian Amazon region. Antimicrobial agents and chemotherapy 61 19451296
2006 Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance. Cellular and molecular life sciences : CMLS 61 16699808
2001 Mutations in the pfmdr1, dhfr and dhps genes of Plasmodium falciparum are associated with in-vivo drug resistance in West Papua, Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene 61 11280065
2016 CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs. Molecular microbiology 60 27073104
2018 Drug-Resistant Polymorphisms and Copy Numbers in Plasmodium falciparum, Mozambique, 2015. Emerging infectious diseases 59 29260689
2012 Various pfcrt and pfmdr1 genotypes of Plasmodium falciparum cocirculate with P. malariae, P. ovale spp., and P. vivax in northern Angola. Antimicrobial agents and chemotherapy 59 22850519
2010 pfmdr1 amplification and fixation of pfcrt chloroquine resistance alleles in Plasmodium falciparum in Venezuela. Antimicrobial agents and chemotherapy 59 20145087
2010 Genetic polymorphism in pvmdr1 and pvcrt-o genes in relation to in vitro drug susceptibility of Plasmodium vivax isolates from malaria-endemic countries. Acta tropica 59 20933490
2014 Expression levels of pvcrt-o and pvmdr-1 are associated with chloroquine resistance and severe Plasmodium vivax malaria in patients of the Brazilian Amazon. PloS one 58 25157811
2013 Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti-malarial drug treatment policy. Malaria journal 58 24172030
2009 In vitro selection of Plasmodium falciparum drug-resistant parasite lines. The Journal of antimicrobial chemotherapy 57 20022938
2025 High Frequency of Artemisinin Partial Resistance Mutations in the Great Lakes Region Revealed Through Rapid Pooled Deep Sequencing. The Journal of infectious diseases 38 39367758
2026 Geographical Heterogeneity in Antimalarial Resistance Markers by Genomic Surveillance in Angola, 2023. The American journal of tropical medicine and hygiene 3 41843937
2026 National genomic profiling of Plasmodium falciparum antimalarial resistance in Zambian children participating in the 2018 malaria indicator survey. Scientific reports 3 42062354
2026 A common DNA deletion altering the 3'UTR of mdr1 is associated with reduced mefloquine susceptibility in P. vivax parasites from Cambodian patients. Nature communications 1 41571698
2026 Asymptomatic malaria: a hidden reservoir for the transmission and circulation of artemisinin partial-resistant Plasmodium falciparum in Tanzania. Emerging microbes & infections 0 41755358
2026 Molecular markers of antimalarial drug resistance in pfk13, pfmdr1, pfdhfr, and pfdhps genes of Plasmodium falciparum in a rural municipality in Cubal, Benguela Province, Angola (2022-2023). Malaria journal 0 41840616
2026 Incidence of kelch13 and Pfmdr1 gene mutations associated with antimalarial drug resistance in Plasmodium falciparum isolates from Ethiopia: a systematic review and meta-analysis. BMC infectious diseases 0 41888692
2026 Spatiotemporal antimalarial drug resistance saturation and emerging artemisinin tolerance in western Kenya during a pilot multiple first-line treatment study. Scientific reports 0 41963472
2026 Hidden Infections, Emerging Resistance: Underdiagnosed Plasmodium vivax and Multidrug Resistance-1 (pvmdr1) Gene Amplification in the Guiana Shield. The Journal of infectious diseases 0 41964524
2026 Molecular detection of chloroquine resistance in Plasmodium vivax isolates from North India: Analysis of single nucleotide polymorphisms in pvmdr1 gene. Molecular and biochemical parasitology 0 42034171
2026 Plasmodium falciparum antimalarial resistance in Angola: a systematic review. Malaria journal 0 42163265
2026 Status of pfcrt and pfmdr1 mutations in Plasmodium falciparum isolates in Gabon in 2019 after chloroquine withdrawal. Acta tropica 0 42176722
2026 Molecular Surveillance of Plasmodium vivax and Plasmodium falciparum Drug Resistance Genes in the Republic of Korea: 2022-2025. Pathogens (Basel, Switzerland) 0 42198634
2026 Structural and mechanistic insights into the inhibition of Plasmodium falciparum MDR1. Nature communications 0 42203772
2026 Geographical Variation in Antimalarial Drug Resistance Marker Prevalence Across the Southern African Elimination Eight Region. medRxiv : the preprint server for health sciences 0 42238473
2026 Droplet digital PCR assays for Pvmdr1 and Pvcrt-o gene copy number variation determination in Plasmodium vivax. Malaria journal 0 42271343
2026 Molecular surveillance of antimalarial drug resistance markers in the pfcrt, pfmdr1 and pfmrp1 genes of Plasmodium falciparum isolates from southeastern Iran. Malaria journal 0 42321796
2026 Mapping the prevalence of molecular markers of Plasmodium falciparum artemisinin partial resistance in Africa: a systematic review and spatiotemporal modelling study. The Lancet. Infectious diseases 0 42413528
2026 Drug resistance gene polymorphisms of Plasmodium falciparum clinical isolates from Kinshasa, Democratic Republic of the Congo. Tropical medicine and health 0 42415199
2026 Genomic surveillance reveals co-occurrence of Plasmodium falciparum drug resistance variants across diverse transmission settings in Ethiopia. Nature microbiology 0 42557356