Plasmodium falciparum Polymorphisms Associated withEx VivoDrug Susceptibility and Clinical Effectiveness of Artemisinin-Based Combination Therapies in Benin

ABSTRACTArtemisinin-based combination therapies (ACTs) are the main option to treat malaria, and their efficacy and susceptibility must be closely monitored to avoid resistance. We assessed the association ofPlasmodium falciparumpolymorphisms andex vivodrug susceptibility with clinical effectiveness. Patients enrolled in an effectiveness trial comparing artemether-lumefantrine (n= 96), fixed-dose artesunate-amodiaquine (n= 96), and sulfadoxine-pyrimethamine (n= 48) for the treatment of uncomplicated malaria 2007 in Benin were assessed.pfcrt,pfmdr1,pfmrp1,pfdhfr, andpfdhpspolymorphisms were analyzed pretreatment and in recurrent infections. Drug susceptibility was determined in fresh baseline isolates byPlasmodiumlactate dehydrogenase enzyme-linked immunosorbent assay (ELISA). A majority had 50% inhibitory concentration (IC50) estimates (the concentration required for 50% growth inhibition) lower than those of the 3D7 reference clone for desethylamodiaquine, lumefantrine, mefloquine, and quinine and was considered to be susceptible, while dihydroartemisinin and pyrimethamine IC50s were higher. No association was found between susceptibility to the ACT compounds and treatment outcome. Selection was observed for thepfmdr1N86 allele in artemether-lumefantrine recrudescences (recurring infections) (4/7 [57.1%] versus 36/195 [18.5%]), and of the opposite allele, 86Y, in artesunate-amodiaquine reinfections (new infections) (20/22 [90.9%] versus 137/195 [70.3%]) compared to baseline infections. The importance ofpfmdr1N86 in lumefantrine tolerance was emphasized by its association with elevated lumefantrine IC50s. Genetic linkage between N86 and Y184 was observed, which together with the low frequency of 1246Y may explain regional differences in selection ofpfmdr1loci. Selection of opposite alleles in artemether-lumefantrine and artesunate-amodiaquine recurrent infections supports the strategy of multiple first-line treatment. Surveillance based on clinical,ex vivo, molecular, and pharmacological data is warranted.

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Associations between Malaria-Preventive Regimens and Plasmodium falciparum Drug Resistance-Mediating Polymorphisms in Ugandan Pregnant Women

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01047-20 ◽

2020 ◽

Vol 64 (12) ◽

Author(s):

Patience Nayebare ◽

Victor Asua ◽

Melissa D. Conrad ◽

Richard Kajubi ◽

Abel Kakuru ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Genetic Polymorphisms ◽

Protective Efficacy ◽

Intermittent Preventive Treatment ◽

Preventive Treatment ◽

Drug Susceptibility ◽

Recent Trial ◽

Content Type ◽

High Level ◽

Selection Of

ABSTRACT Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of Plasmodium falciparum genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%; P < 0.001), PfMDR1 Y184F (73.0% versus 53.0%; P < 0.001), and PfCRT K76T (46.4% versus 24.0%; P < 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; P = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; P = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility.

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Ex VivoActivity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02462-14 ◽

2014 ◽

Vol 58 (10) ◽

pp. 5831-5840 ◽

Cited By ~ 8

Author(s):

Charlotte A. Lanteri ◽

Suwanna Chaorattanakawee ◽

Chanthap Lon ◽

David L. Saunders ◽

Wiriya Rutvisuttinunt ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Ex Vivo ◽

Geometric Mean ◽

Artemisinin Resistance ◽

Multidrug Resistant ◽

Chloroquine Resistance ◽

Enzyme Linked Immunosorbent Assay ◽

Multidrug Resistance Gene ◽

Content Type ◽

Clinical Resistance

ABSTRACTNovel synthetic endoperoxides are being evaluated as new components of artemisinin combination therapies (ACTs) to treat artemisinin-resistantPlasmodium falciparummalaria. We conducted blindedex vivoactivity testing of fully synthetic (OZ78 and OZ277) and semisynthetic (artemisone, artemiside, artesunate, and dihydroartemisinin) endoperoxides in the histidine-rich protein 2 enzyme-linked immunosorbent assay against 200P. falciparumisolates from areas of artemisinin-resistant malaria in western and northern Cambodia in 2009 and 2010. The order of potency and geometric mean (GM) 50% inhibitory concentrations (IC50s) were as follows: artemisone (2.40 nM) > artesunate (8.49 nM) > dihydroartemisinin (11.26 nM) > artemiside (15.28 nM) > OZ277 (31.25 nM) > OZ78 (755.27 nM).Ex vivoactivities of test endoperoxides positively correlated with dihydroartemisinin and artesunate. The isolates were over 2-fold less susceptible to dihydroartemisinin than the artemisinin-sensitiveP. falciparumW2 clone and showed sensitivity comparable to those with test endoperoxides and artesunate, with isolate/W2 IC50susceptibility ratios of <2.0. All isolates hadP. falciparumchloroquine resistance transporter mutations, with negative correlations in sensitivity to endoperoxides and chloroquine. The activities of endoperoxides (artesunate, dihydroartemisinin, OZ277, and artemisone) significantly correlated with that of the ACT partner drug, mefloquine. Isolates had mutations associated with clinical resistance to mefloquine, with 35% prevalence ofP. falciparummultidrug resistance gene 1 (pfmdr1) amplification and 84.5% occurrence of thepfmdr1Y184F mutation. GM IC50s for mefloquine, lumefantrine, and endoperoxides (artesunate, dihydroartemisinin, OZ277, OZ78, and artemisone) correlated withpfmdr1copy number. Given that current ACTs are failing potentially from reduced sensitivity to artemisinins and partner drugs, newly identified mutations associated with artemisinin resistance reported in the literature andpfmdr1mutations should be examined for their combined contributions to emerging ACT resistance.

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ComparativeEx VivoActivity of Novel Endoperoxides in Multidrug-Resistant Plasmodium falciparum and P. vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00283-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5258-5263 ◽

Cited By ~ 33

Author(s):

Jutta Marfurt ◽

Ferryanto Chalfein ◽

Pak Prayoga ◽

Frans Wabiser ◽

Grennady Wirjanata ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Activity ◽

Ex Vivo ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Intrinsic Activity ◽

Drug Resistant ◽

The Novel ◽

Content Type ◽

Artemisinin Derivatives

ABSTRACTThe declining efficacy of artemisinin derivatives againstPlasmodium falciparumhighlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against bothP. falciparumandP. vivaxmalaria, comparativeex vivoantimalarial activity againstPlasmodiumisolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP).Ex vivodrug susceptibility was assessed in 46 field isolates (25P. falciparumand 21P. vivax). The novel endoperoxide compounds exhibited potentex vivoactivity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC50s) in both species (median IC50s between 1.9 and 3.6 nM inP. falciparumand 0.7 and 4.6 nM inP. vivax). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the twoPlasmodiumspecies: whereas theirex vivoactivity correlated positively with CQ, PIP, AS, and DHA inP. falciparum, the same was not apparent inP. vivax. The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistantP. vivax. The high activity against drug-resistant strains of bothPlasmodiumspecies confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.

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Ex VivoDrug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00366-15 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4631-4643 ◽

Cited By ~ 46

Author(s):

Suwanna Chaorattanakawee ◽

David L. Saunders ◽

Darapiseth Sea ◽

Nitima Chanarat ◽

Kritsanai Yingyuen ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Antimalarial Activity ◽

Ex Vivo ◽

Artemisinin Combination Therapy ◽

Artemisinin Resistance ◽

Drug Susceptibility ◽

Chloroquine Resistance ◽

First Line ◽

Content Type

ABSTRACTCambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistantPlasmodium falciparummalaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying forex vivodrug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence ofP. falciparummultidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of theP. falciparumchloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years hadP. falciparumkelch13mutations, indicative of artemisinin resistance.Ex vivobioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantialin vivodrug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of theP. falciparummdr1copy number, as a stop-gap measure in areas of DHA-PPQ failure.

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PotentEx VivoActivity of Naphthoquine and Methylene Blue against Drug-Resistant Clinical Isolates of Plasmodium falciparum and Plasmodium vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00874-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6117-6124 ◽

Cited By ~ 12

Author(s):

Grennady Wirjanata ◽

Boni F. Sebayang ◽

Ferryanto Chalfein ◽

Prayoga ◽

Irene Handayuni ◽

...

Keyword(s):

Methylene Blue ◽

Plasmodium Falciparum ◽

Ex Vivo ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Trophozoite Stage ◽

Content Type ◽

Susceptibility Data ◽

Highly Active

ABSTRACTThe 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potentin vitroefficacies againstPlasmodium falciparum, but susceptibility data forP. vivaxare limited. The species- and stage-specificex vivoactivities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistantP. falciparumandP. vivaxare prevalent. Both compounds were highly active againstP. falciparum(median [range] 50% inhibitory concentration [IC50]: NQ, 8.0 nM [2.6 to 71.8 nM]; and MB, 1.6 nM [0.2 to 7.0 nM]) andP. vivax(NQ, 7.8 nM [1.5 to 34.2 nM]; and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC50s in parasites exposed at the trophozoite stage than at the ring stage for NQ inP. falciparum(26.5 versus 5.1 nM,P= 0.021) andP. vivax(341.6 versus 6.5 nM,P= 0.021) and for MB inP. vivax(10.1 versus 1.6 nM,P= 0.010). The excellentex vivoactivities of NQ and MB against bothP. falciparumandP. vivaxhighlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.

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Combined Transcriptome and Proteome Profiling for Role of pfEMP1 in Antimalarial Mechanism of Action of Dihydroartemisinin

Microbiology Spectrum ◽

10.1128/spectrum.01278-21 ◽

2021 ◽

Author(s):

Lina Chen ◽

Zhongyuan Zheng ◽

Hui Liu ◽

Xi Wang ◽

Shuiqing Qu ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mechanism Of Action ◽

Blood Cells ◽

Artemisinin Derivative ◽

Combination Therapies ◽

Proteomic Profiling ◽

First Line ◽

Content Type ◽

Artemisinin Combination Therapies

Malaria parasites induce morphological and biochemical changes in the membranes of parasite-infected red blood cells (iRBCs) for propagation, with artemisinin combination therapies as the first-line treatments. To understand whether artemisinin targets or interacts with iRBC membrane proteins, this study investigated the molecular changes caused by dihydroartemisinin (DHA), an artemisinin derivative, in Plasmodium falciparum 3D7 using a combined transcriptomic and membrane proteomic profiling approach.

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Tolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate Assay

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00720-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e00720-20

Author(s):

Haddijatou Mbye ◽

Fatoumata Bojang ◽

Aminata Seedy Jawara ◽

Bekai Njie ◽

Nuredin Ibrahim Mohammed ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Survival Rate ◽

Drug Exposure ◽

Ex Vivo ◽

Ring Stage ◽

Color Flow ◽

Continuous Growth ◽

Content Type ◽

Parasite Survival ◽

Survival Assay

ABSTRACTMonitoring of Plasmodium falciparum sensitivity to antimalarial drugs in Africa is vital for malaria elimination. However, the commonly used ex vivo/in vitro 50% inhibitory concentration (IC50) test gives inconsistent results for several antimalarials, while the alternative ring-stage survival assay (RSA) for artemisinin derivatives has not been widely adopted. Here, we applied an alternative two-color flow cytometry-based parasite survival rate assay (PSRA) to detect ex vivo antimalarial tolerance in P. falciparum isolates from The Gambia. The PSRA infers parasite viability by quantifying reinvasion of uninfected cells following 3 consecutive days of drug exposure (10-fold the IC50 of drug for field isolates). The drug survival rate is obtained for each isolate from the slope of the growth/death curve. We obtained parasite survival rates of 41 isolates for dihydroartemisinin (DHA) and lumefantrine (LUM) out of 51 infections tested by ring-stage survival assay (RSA) against DHA. We also determined the genotypes for known drug resistance genetic loci in the P. falciparum genes Pfdhfr, Pfdhps, Pfmdr, Pfcrt, and Pfk13. The PSRA results determined for 41 Gambian isolates showed faster killing and lower variance after treatment with DHA than after treatment with LUM, despite a strong correlation between the two drugs. Four and three isolates were tolerant to DHA and LUM, respectively, with continuous growth during drug exposure. Isolates with the PfMDR1-Y184F mutant variant showed increased LUM survival, though the results were not statistically significant. Sulfadoxine/pyrimethamine (SP) resistance markers were fixed, while all other antimalarial variants were prevalent in more than 50% of the population. The PSRA detected ex vivo antimalarial tolerance in Gambian P. falciparum. This calls for its wider application and for increased vigilance against resistance to artemisinin combination therapies (ACTs) in this population.

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Decreased susceptibility to dihydrofolate reductase inhibitors associated with genetic polymorphisms in Ugandan Plasmodium falciparum isolates

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab435 ◽

2021 ◽

Author(s):

Oriana Kreutzfeld ◽

Patrick K Tumwebaze ◽

Oswald Byaruhanga ◽

Thomas Katairo ◽

Martin Okitwi ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Dihydrofolate Reductase ◽

Ex Vivo ◽

Drug Susceptibility ◽

Mixed Genotype ◽

Susceptibility Data ◽

Reductase Inhibitors ◽

Excellent Activity ◽

Quadruple Mutant ◽

Dihydrofolate Reductase Inhibitors

Abstract Background The Plasmodium falciparum dihydrofolate reductase (PfDHFR) inhibitors pyrimethamine and cycloguanil (the active metabolite of proguanil) have important roles in malaria chemoprevention, but drug resistance challenges their efficacies. A new compound, P218, was designed to overcome resistance, but drug susceptibility data for P. falciparum field isolates are limited. Methods We studied ex vivo PfDHFR inhibitor susceptibilities of 559 isolates from Tororo and Busia districts, Uganda from 2016-2020, sequenced 383 isolates, and assessed associations between genotypes and drug susceptibility phenotypes. Results Median IC50’s were 42,100 nM for pyrimethamine, 1,200 nM for cycloguanil, 13,000 nM for proguanil, and 0.6 nM for P218. Among sequenced isolates, three PfDHFR mutations, 51I (100%), 59R (93.7%), and 108N (100%), were very common, as previously seen in Uganda, and another mutation, 164L (12.8%), had moderate prevalence. Increasing numbers of mutations were associated with decreasing susceptibility to pyrimethamine, cycloguanil, and P218, but not proguanil, which does not act directly against PfDHFR. Differences in P218 susceptibilities were modest, with median IC50 1.4 nM for parasites with mixed genotype at position 164 and 5.7 nM for pure quadruple mutant (51I/59R/108N/164L) parasites. Conclusion Resistance-mediating PfDHFR mutations were common in Ugandan isolates, but P218 retained excellent activity against mutant parasites.

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Molecular Surveillance of Drug Resistance of Plasmodium falciparum Isolates Imported from Angola in Henan Province, China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00552-19 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 1

Author(s):

Ruimin Zhou ◽

Chengyun Yang ◽

Suhua Li ◽

Yuling Zhao ◽

Ying Liu ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Henan Province ◽

Nucleotide Polymorphisms ◽

Combination Therapies ◽

Antimalarial Drug Resistance ◽

Single Nucleotide ◽

Molecular Surveillance ◽

Content Type

ABSTRACT Angola was the main origin country for the imported malaria in Henan Province, China. Antimalarial drug resistance has posed a threat to the control and elimination of malaria. Several molecular markers were confirmed to be associated with the antimalarial drug resistance, such as pfcrt, pfmdr1, pfdhfr, pfdhps, and K13. This study evaluated the drug resistance of the 180 imported Plasmodium falciparum isolates from Angola via nested PCR using Sanger sequencing. The prevalences of pfcrt C72V73M74N75K76, pfmdr1 N86Y184S1034N1042D1246, pfdhfr A16N51C59S108D139I164, and pfdhps S436A437A476K540A581 were 69.4%, 59.9%, 1.3% and 6.3%, respectively. Three nonsynonymous (A578S, M579I, and Q613E) and one synonymous (R471R) mutation of K13 were found, the prevalences of which were 2.5% and 1.3%, respectively. The single nucleotide polymorphisms (SNPs) in pfcrt, pfmdr1, pfdhfr, and pfdhps were generally shown as multiple mutations. The mutant prevalence of pfcrt reduced gradually, but pfdhfr and pfdhps still showed high mutant prevalence, while pfmdr1 was relatively low. The mutation of the K13 gene was rare. Molecular surveillance of artemisinin (ART) resistance will be used as a tool to evaluate the real-time efficacy of the artemisinin-based combination therapies (ACTs) and the ART resistance situation.

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Expansion of a Specific Plasmodium falciparum PfMDR1 Haplotype in Southeast Asia with Increased Substrate Transport

mBio ◽

10.1128/mbio.02093-20 ◽

2020 ◽

Vol 11 (6) ◽

Author(s):

Carla Calçada ◽

Miguel Silva ◽

Vitória Baptista ◽

Vandana Thathy ◽

Rita Silva-Pedrosa ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Multidrug Resistance ◽

Southeast Asia ◽

Gene Copy ◽

Multidrug Resistance Protein ◽

Combination Therapies ◽

Transport Capacity ◽

Multidrug Resistance Protein 1 ◽

Content Type ◽

Resistance Protein

ABSTRACT Artemisinin-based combination therapies (ACTs) have been vital in reducing malaria mortality rates since the 2000s. Their efficacy, however, is threatened by the emergence and spread of artemisinin resistance in Southeast Asia. The Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter plays a central role in parasite resistance to ACT partner drugs through gene copy number variations (CNV) and/or single nucleotide polymorphisms (SNPs). Using genomic epidemiology, we show that multiple pfmdr1 copies encoding the N86 and 184F haplotype are prevalent across Southeast Asia. Applying genome editing tools on the Southeast Asian Dd2 strain and using a surrogate assay to measure transporter activity in infected red blood cells, we demonstrate that parasites harboring multicopy N86/184F PfMDR1 have a higher Fluo-4 transport capacity compared with those expressing the wild-type N86/Y184 haplotype. Multicopy N86/184F PfMDR1 is also associated with decreased parasite susceptibility to lumefantrine. These findings provide evidence of the geographic selection and expansion of specific multicopy PfMDR1 haplotypes associated with multidrug resistance in Southeast Asia. IMPORTANCE Global efforts to eliminate malaria depend on the continued success of artemisinin-based combination therapies (ACTs) that target Plasmodium asexual blood-stage parasites. Resistance to ACTs, however, has emerged, creating the need to define the underlying mechanisms. Mutations in the P. falciparum multidrug resistance protein 1 (PfMDR1) transporter constitute an important determinant of resistance. Applying gene editing tools combined with an analysis of a public database containing thousands of parasite genomes, we show geographic selection and expansion of a pfmdr1 gene amplification encoding the N86/184F haplotype in Southeast Asia. Parasites expressing this PfMDR1 variant possess a higher transport capacity that modulates their responses to antimalarials. These data could help tailor and optimize antimalarial drug usage in different regions where malaria is endemic by taking into account the regional prevalence of pfmdr1 polymorphisms.

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