Affinage · Plasmodium

Kelch13

PF3D7_1343700 · kelch protein K13

Annotated
2026-09-08
100 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Kelch13 (PF3D7_1343700) is an essential BTB/POZ- and kelch-propeller-domain protein of Plasmodium falciparum that governs hemoglobin endocytosis and cellular proteostasis, and whose propeller-domain mutations are the principal genetic determinant of artemisinin resistance (PMID:24352242, PMID:25502314, PMID:31896710). Reciprocal gene editing across multiple parasite backgrounds established that propeller-domain mutations (e.g. C580Y, R561H, R539T, M579I) are causally sufficient to confer ring-stage artemisinin survival, that their effect and fitness cost depend on genetic background, and that these alleles have emerged independently in Southeast Asia, Africa (Rwanda) and South America (Guyana) (PMID:25502314, PMID:34279219, PMID:32747827, PMID:32394893). Mechanistically, Kelch13 defines an endosomal/vesicular compartment where it drives hemoglobin uptake from the host red cell via the cytostome pathway; because artemisinins are activated by hemoglobin-derived heme, mutation- or mislocalization-induced loss of Kelch13 function reduces hemoglobin endocytosis and thereby lowers drug activation, and this partial loss of function is accompanied by reduced Kelch13 protein abundance (PMID:31775055, PMID:31896710, PMID:28368494). Kelch13 also binds PfPI3K and promotes its polyubiquitination and proteolysis, so that resistance mutations elevate PfPI3K and its lipid product PI3P, a change predictive of resistance and associated with altered PI3P vesicle/tubule networks and PfEMP1 export (PMID:25874676, PMID:29363540). Consistent with a proteostasis role, artemisinin engages the ubiquitin/proteasome stress response, Kelch13-mutant parasites mount an attenuated proteotoxic response, and proteasome inhibition synergizes with artemisinin (PMID:25901609); systems-level analyses link Kelch13 mutations to altered cell-cycle periodicity, the unfolded protein response, vesicular trafficking and mitochondrial metabolism (PMID:33483501). Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes, and relocalizes toward the mitochondrion upon dihydroartemisinin exposure (PMID:31775055, PMID:32310999).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2013 High

    Established the first genetic marker of artemisinin resistance by linking a specific parasite locus to the clinical phenotype, previously defined only by delayed parasite clearance.

    Evidence Whole-genome sequencing of a resistant line plus in vitro survival and in vivo clearance measurements in Cambodian isolates

    PMID:24352242

    Open questions at the time
    • Association only — did not prove causality
    • No molecular function assigned to Kelch13
    • Mechanism of resistance unknown
  2. 2014 High

    Proved that Kelch13 propeller mutations are causally sufficient for resistance, moving the field from correlation to causation.

    Evidence Zinc-finger nuclease reciprocal editing (insertion and removal of mutations) with ring-stage survival readout

    PMID:25502314

    Open questions at the time
    • Did not define the biochemical function of Kelch13
    • Did not identify how mutations alter protein activity
  3. 2015 High

    Provided a biochemical mechanism by identifying PfPI3K as a Kelch13 target whose ubiquitin-dependent turnover controls PI3P, and mutations relieve this control.

    Evidence Binding and polyubiquitination assays plus PfPI3K/PI3P quantification in resistant strains and drug susceptibility assays

    PMID:25874676

    Open questions at the time
    • Ubiquitin ligase machinery not fully defined
    • Relationship between PI3P elevation and hemoglobin/heme pathway not integrated
    • Single lab for the biochemical reconstitution
  4. 2015 High

    Connected resistance to an attenuated proteotoxic stress response and revealed a therapeutic vulnerability via proteasome inhibition.

    Evidence Ubiquitinated-protein and cell-death kinetics plus proteasome-inhibitor synergy in isogenic lines, cross-validated in vivo in P. berghei

    PMID:25901609

    Open questions at the time
    • Did not directly link Kelch13 to proteasome regulation mechanistically
    • Which stress-response components are Kelch13-dependent unclear
  5. 2017 Medium

    Confirmed Kelch13 essentiality and enabled functional dissection via inducible inactivation and mislocalization of the native protein.

    Evidence Selection-linked integration with DiCre excision and knock-sideways mislocalization plus microscopy

    PMID:28288121

    Open questions at the time
    • Single lab, single study
    • Did not resolve the essential molecular activity
    • Essentiality vs. partial-loss-of-function distinction for resistance not addressed here
  6. 2017 Medium

    Multi-omics tied Kelch13 mutations to reduced Kelch13 protein, decreased hemoglobin digestion, and altered redox metabolism, foreshadowing the hemoglobin-uptake mechanism.

    Evidence LC-MS proteomics, peptidomics and metabolomics of isogenic mutant vs wild-type lines

    PMID:28368494

    Open questions at the time
    • Correlative, did not establish the endocytic step
    • Single lab
  7. 2018 Medium

    Placed Kelch13 at PI3P-rich ER tubules/vesicles and linked its mutation to altered PI3P networks and virulence-adhesin (PfEMP1) export.

    Evidence Cryo-immunoEM, colocalization/copurification with PfEMP1, PI3P vesicle quantification and cytoadherence assays in K13 mutants

    PMID:29363540

    Open questions at the time
    • Functional significance of PfEMP1 copurification for resistance unresolved
    • Single lab
    • Direct vs indirect Kelch13–PI3P relationship not separated
  8. 2020 High

    Defined the central cellular mechanism: Kelch13 marks an endocytic compartment mediating hemoglobin uptake, and its dysfunction reduces heme-dependent artemisinin activation.

    Evidence Identification of Kelch13-compartment proteins, genetic inactivation, hemoglobin endocytosis and ring-stage survival assays

    PMID:31896710

    Open questions at the time
    • Precise molecular role of Kelch13 within the endocytic machinery not defined
    • How mutations mechanistically impair endocytosis unresolved
  9. 2020 High

    Refined Kelch13 subcellular localization (ER, Rab vesicles, adjacent to cytostomes) and its dynamic relocalization to the mitochondrion under drug pressure, plus reversal of mutant resistance by wild-type co-expression.

    Evidence Kelch13-specific monoclonal antibodies, epitope-tagged lines, quantitative imaging, immunoprecipitation and RSA

    PMID:32310999

    Open questions at the time
    • Functional meaning of mitochondrial relocalization unclear
    • Putative interactors from IP not individually validated
    • Single lab
  10. 2020 High

    Localized Kelch13 to peripheral cytostome-like structures and showed mislocalization phenocopies resistance mutations, establishing partial loss of function as the operative event.

    Evidence GFP tagging, knock-sideways mislocalization, pulse-SILAC turnover and hemoglobin peptidomics

    PMID:31775055

    Open questions at the time
    • Threshold of Kelch13 activity needed for sensitivity not quantified
    • Mechanistic link between abundance and endocytic rate incomplete
  11. 2020 High

    Documented emergence and causality of specific propeller mutations across geographies (Rwanda R561H; Guyana C580Y/R539T; China-Myanmar F446I/N458Y), and showed resistance can also arise Kelch13-independently.

    Evidence CRISPR editing/reversion across strains with RSA and competition assays; long-term in vitro selection yielding pfk13-wild-type resistance

    PMID:29538461 PMID:32098812 PMID:32394893 PMID:32747827

    Open questions at the time
    • Kelch13-independent resistance mechanisms not molecularly defined
    • Determinants of geographic mutation preference unclear
  12. 2021 High

    Showed the resistance effect and fitness cost of Kelch13 mutations are strongly genetic-background dependent, explaining differential spread of alleles.

    Evidence Gene editing of R561H/C580Y/M579I into African and Southeast Asian backgrounds with RSA and fitness competition

    PMID:34279219

    Open questions at the time
    • Modifier loci that permit low-cost resistance not identified
    • Molecular basis of background dependence unknown
  13. 2021 High

    Systems profiling broadened the Kelch13-mutant phenotype to cell-cycle, UPR, trafficking and mitochondrial metabolism, with atovaquone reversing resistance and implicating mitochondrial processes.

    Evidence Quantitative transcriptomics/proteomics/metabolomics on isogenic panel plus atovaquone reversal and RSA

    PMID:33483501

    Open questions at the time
    • Causal chain from Kelch13 to mitochondrial metabolism not established
    • Whether mitochondrial involvement is direct or downstream unclear
  14. 2017 High

    Defined the cross-resistance spectrum, showing Kelch13 mutations confer resistance to the ozonide OZ277 but not generally to OZ439, informing endoperoxide drug design.

    Evidence RSA with DHA, OZ277 and OZ439 plus competition assays in gene-edited isogenic lines

    PMID:28400526

    Open questions at the time
    • Structural basis for differential ozonide cross-resistance unknown
  15. 2020 Medium

    Correlated an in vitro delayed-clearance assay with in vivo clearance and Kelch13 genotype, tracing resistance to altered stage-specific drug exposure across the cell cycle.

    Evidence In vitro delayed clearance assay with stage-specific exposure quantification and K13 genotyping

    PMID:25779582

    Open questions at the time
    • Correlative link between cell-cycle timing and Kelch13 function not mechanistic
    • Single lab
  16. 2026 Medium

    Extended causal validation to Bangladeshi backgrounds, showing C580Y/R561H confer strong resistance with minimal fitness cost and, for R561H in a resistant background, a growth advantage.

    Evidence CRISPR-Cas9 editing into two Bangladeshi isolates with RSA, recovery and competitive fitness assays

    PMID:41841738

    Open questions at the time
    • Single lab, single study
    • Mechanism of the R561H growth advantage undefined
    • Interaction with the K13-independent resistance background unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise molecular activity of Kelch13 within the endocytic/vesicular machinery and how propeller mutations mechanistically reduce hemoglobin uptake and integrate PI3P, proteostasis and mitochondrial changes remain unresolved.
  • No structural model of mutant vs wild-type propeller function reconciling all phenotypes
  • Ubiquitin-ligase and endocytic partners incompletely defined
  • Unified causal chain linking hemoglobin uptake, PI3P, UPR and mitochondrial metabolism missing

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
PFEMP1 (COLOCALIZES AND COPURIFIES WITH KELCH13) [#7]PFPI3K (BOUND AND TARGETED FOR POLYUBIQUITINATION/PROTEOLYSIS BY KELCH13) [#2]RAB GTPASES AND ER-RESIDENT AND MITOCHONDRIAL PROTEINS (PUTATIVE KELCH13-ASSOCIATED PROTEINS BY IMMUNOPRECIPITATION) [#6]
Complex memberships
Kelch13-defined endosomal/vesicular compartment (Kelch13 plus eight compartment proteins whose loss confers artemisinin resistance) [#5]

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 Mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') are associated with artemisinin resistance in vitro and in vivo. Using whole-genome sequencing of an artemisinin-resistant parasite line and clinical isolates, mutant K13-propeller alleles were found to cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant allele correlates with the recent spread of resistance in western Cambodia. Whole-genome sequencing of artemisinin-resistant parasite line; in vitro parasite survival assays; in vivo parasite clearance rate measurements in patients Nature High 24352242
2014 Genetic modification of the Kelch13 locus using zinc-finger nucleases demonstrated that K13 mutations are causally sufficient to confer artemisinin resistance. Removal of K13 mutations from resistant Cambodian isolates reduced ring-stage survival rates from 13–49% to 0.3–2.4%, while insertion of K13 mutations into wild-type parasites increased survival rates from ≤0.6% to 2–29%. Zinc-finger nuclease-mediated genetic modification of the Kelch13 locus in P. falciparum; ring-stage survival assay (RSA) Science High 25502314
2015 Kelch13 (PfKelch13) binds to and promotes polyubiquitination and proteolysis of PfPI3K. The C580Y resistance mutation in Kelch13 reduces polyubiquitination of PfPI3K and its binding to Kelch13, limiting PfPI3K proteolysis and thereby increasing PfPI3K levels and its lipid product phosphatidylinositol-3-phosphate (PI3P). Elevated PI3P was shown to be predictive of artemisinin resistance. Biochemical binding assays; polyubiquitination assays; measurement of PfPI3K protein levels and PI3P lipid levels in resistant clinical strains vs. wild-type; in vitro and in vivo artemisinin susceptibility assays Nature High 25874676
2015 Kelch13 mutations result in decreased expression of the Kelch13 protein, and mislocalization of Kelch13 (using a knock-sideways approach) mimics resistance-conferring mutations, indicating that partial loss of function of Kelch13 is the relevant molecular event for resistance. Kelch13-GFP localizes to ~170 nm diameter doughnut-shaped structures at the parasite periphery consistent with cytostomes. Mislocalization of Kelch13 reduces the hemoglobin-peptide profile of ring-stage parasites and reduces disruption to protein turnover following artemisinin exposure. Mislocalization (knock-sideways) of Kelch13 using GFP tagging; fluorescence microscopy; pulse-SILAC protein turnover quantification; peptidomics of hemoglobin-derived peptides Cell reports High 31775055
2017 Using selection-linked integration (SLI), Kelch13 was localized and inducibly inactivated in P. falciparum. Inducible inactivation of Kelch13 demonstrated it is an essential protein. The SLI approach allowed functional analysis at gene and protein levels including mislocalization of the native protein. Selection-linked integration (SLI) for genomic integration; knock-sideways mislocalization; DiCre-based conditional gene excision; fluorescence microscopy Nature methods Medium 28288121
2020 Kelch13 defines a specific endosomal/vesicular compartment in P. falciparum. Inactivation of Kelch13 or expression of a resistance-conferring Kelch13 mutation reduced hemoglobin endocytosis from the host red cell. Since artemisinins are activated by hemoglobin degradation products (heme), reduced hemoglobin endocytosis caused by Kelch13 dysfunction leads to decreased artemisinin activation and parasite resistance. Eight Kelch13-compartment proteins were identified whose inactivation also rendered parasites resistant to artemisinin. Identification of Kelch13-compartment proteins; genetic inactivation of Kelch13 and interactors; hemoglobin endocytosis assays; ring-stage survival assays Science High 31896710
2020 Kelch13 localizes to the parasite endoplasmic reticulum, Rab-positive vesicles, and sites adjacent to cytostomes (which traffic hemoglobin to the digestive vacuole). Upon treatment with dihydroartemisinin, Kelch13 partially relocalizes near the parasite mitochondria. Immunoprecipitation with Kelch13-specific monoclonal antibodies identified multiple putative Kelch13-associated proteins including ER-resident molecules, mitochondrial proteins, and Rab GTPases. Co-expression of wild-type Kelch13 reversed mutant Kelch13-mediated resistance. K13-specific monoclonal antibodies; gene-edited parasite lines co-expressing epitope-tagged Kelch13; quantitative imaging pipeline; immunoprecipitation; fluorescence microscopy; ring-stage survival assay PLoS pathogens High 32310999
2018 Kelch13 concentrates at PI3P tubules/vesicles of the parasite's endoplasmic reticulum in infected red cells. Kelch13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The C580Y resistance mutation quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Multiple Kelch13 mutants showed alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor. Cryoimmunoelectron microscopy; colocalization and copurification experiments; PI3P vesicle quantification; PfEMP1 export and cytoadherence assays in K13 mutant parasites Blood Medium 29363540
2017 Multi-omics profiling of PfKelch13-mutant artemisinin-resistant vs. sensitive P. falciparum strains revealed that Kelch13 mutations are specifically associated with decreased abundance of Kelch13 protein itself, decreased hemoglobin digestion (lower abundance of hemoglobin-derived peptides), and enhanced glutathione production. LC-MS-based proteomics, peptidomics, and metabolomics of isogenic Kelch13 mutant and wild-type parasite lines The Journal of infectious diseases Medium 28368494
2021 Systems-based quantitative transcriptomics, proteomics, and metabolomics applied to isogenic Kelch13 mutant and wild-type P. falciparum lines showed that Kelch13 mutations alter multiple aspects of the parasite's intra-erythrocytic developmental program, including cell-cycle periodicity, unfolded protein response, protein degradation, vesicular trafficking, and mitochondrial metabolism. Kelch13-mediated resistance in the Cambodian Cam3.II line was reversed by atovaquone (a mitochondrial electron transport chain inhibitor), implicating mitochondrial processes in resistance. Isogenic K13 mutant panel; quantitative transcriptomics, proteomics, and metabolomics; atovaquone reversal experiment; ring-stage survival assay Nature communications High 33483501
2020 PfKelch13 protein is expressed ubiquitously in all asexual erythrocytic stages and in gametocytes, and localizes to punctate structures partially overlapping an endoplasmic reticulum marker. Introduction of four PfKelch13 mutations (F446I, N458Y, C469Y, F495L) from China-Myanmar border parasites into the 3D7 strain showed higher RSA survival rates, with N458Y yielding the most significant increase (26.3%). Reversion of these mutations in field isolates reduced RSA values. F446I caused prolonged ring-stage development with minimal fitness cost. GFP-tagging of PfKelch13; new anti-PfKelch13 antibody; fluorescence microscopy; CRISPR-based mutation introduction and reversion; ring-stage survival assay; in vitro culture competition assays mBio Medium 32098812
2021 Gene editing of multiple Kelch13 mutations (including R561H, C580Y, M579I) into African (3D7) and Southeast Asian (Dd2 and other) P. falciparum strain backgrounds showed that the resistance conferred by Kelch13 mutations depends on genetic background. C580Y and M579I cause substantial fitness costs in most backgrounds but not in recent Cambodian strains; R561H is fitness neutral in African 3D7 parasites. Only R561H yielded ART resistance comparable to C580Y when edited into Southeast Asian strains. Gene editing (introduction of K13 mutations into multiple strain backgrounds); ring-stage survival assay; mixed-culture fitness competition assays eLife High 34279219
2015 ART treatment induces growth retardation and accumulation of ubiquitinated proteins in wild-type parasites, indicative of a cellular stress response engaging the ubiquitin/proteasome system. Resistant parasites carrying K13 propeller mutations exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. Inhibiting the proteasome strongly synergizes ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type Kelch13. Kinetic analysis of drug responses; measurement of ubiquitinated protein levels; proteasome inhibitor synergy assays in K13 wild-type and mutant isogenic lines; P. berghei in vivo synergy experiments PLoS biology High 25901609
2017 Kelch13 mutations (C580Y, R539T, I543T) confer cross-resistance to the ozonide OZ277 (arterolane) in addition to dihydroartemisinin. However, OZ439 (artefenomel) retains activity against most K13 mutant parasites (cross-resistance only observed for the rare I543T mutation). K13 mutations showed variable impacts on parasite growth rates depending on the specific mutation and parasite strain, with the prevalent C580Y mutation being fitness neutral in recently culture-adapted Cambodian strains. Ring-stage survival assay (RSA0-3h) with DHA, OZ439, and OZ277; mixed-culture competition experiments with isogenic K13 lines; gene-edited clinical isolates from Cambodia mBio High 28400526
2020 Gene editing confirmed that the Kelch13 R561H mutation drives artemisinin resistance in vitro in P. falciparum, providing evidence for de novo emergence of Kelch13-mediated artemisinin resistance in Rwanda. Gene editing (introduction of R561H mutation into P. falciparum); ring-stage survival assay Nature medicine High 32747827
2020 In vitro artemisinin resistance can emerge independently of Kelch13 mutations in P. falciparum, as shown by long-term in vitro selection that induced profound stage-specific resistance with no pfk13 mutations, associated instead with enhanced adaptive responses against oxidative stress and protein damage. Long-term in vitro selection for artemisinin resistance; chemosensitivity assays; transcriptional profiling; whole-genome sequencing PLoS pathogens Medium 29538461
2020 In vitro emergence of Kelch13 C580Y mutations in Guyana (South America) in parasites with a genetic origin distinct from Southeast Asia was demonstrated. Introducing C580Y or R539T mutations by gene editing into local Guyanese parasites conferred high levels of in vitro artemisinin resistance. In vitro growth competition assays revealed a fitness cost associated with these Kelch13 variants. Genome analysis; gene editing (CRISPR) to introduce C580Y and R539T into local P. falciparum; ring-stage survival assay; in vitro growth competition assays eLife High 32394893
2020 In vitro artemisinin resistance assay (delayed clearance assay/DCA) results correlated with parasite clearance half-life in vivo and with mutations in the Kelch13 domain gene (Pf3D7_1343700). Artemisinin-resistant P. falciparum parasites exhibited altered patterns of development resulting in reduced exposure to drug at the trophozoite stage and increased exposure in the ring stage, indicating an altered cell cycle mechanism for resistance. In vitro delayed clearance assay (DCA); stage-specific drug exposure quantification; correlation with in vivo clearance half-life; K13 genotyping Antimicrobial agents and chemotherapy Medium 25779582
2026 Introduction of globally dominant Kelch13 mutations (C580Y, R561H, F446I) by CRISPR-Cas9 into two Bangladeshi P. falciparum isolates (including a K13-independent resistant strain) demonstrated that C580Y and R561H confer marked increases in artemisinin resistance in both backgrounds, while F446I had only modest effects. R561H in the resistant background conferred extreme resistance (RSA 30.09%) and an asexual growth advantage. All three mutations incurred minimal fitness costs in the artemisinin-sensitive background. CRISPR-Cas9 gene editing; ring-stage survival assay; post-treatment recovery assays; competitive fitness assays mBio Medium 41841738

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Spread of artemisinin resistance in Plasmodium falciparum malaria. The New England journal of medicine 1669 25075834
2013 A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 1583 24352242
2021 Evidence of Artemisinin-Resistant Malaria in Africa. The New England journal of medicine 644 34551228
2020 Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum kelch13 R561H mutant parasites in Rwanda. Nature medicine 606 32747827
2014 Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science (New York, N.Y.) 567 25502314
2015 Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nature genetics 471 25599401
2016 A Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms. The New England journal of medicine 453 27332904
2015 A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature 423 25874676
2016 Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. The Lancet. Infectious diseases 402 26774243
2017 The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study. The Lancet. Infectious diseases 374 28161569
2014 Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. The Journal of infectious diseases 357 25180241
2021 Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: an open-label, single-arm, multicentre, therapeutic efficacy study. The Lancet. Infectious diseases 337 33864801
2017 Antimalarial Drug Resistance: A Threat to Malaria Elimination. Cold Spring Harbor perspectives in medicine 335 28289248
2020 A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science (New York, N.Y.) 332 31896710
2015 Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker. The Lancet. Infectious diseases 332 25704894
2015 Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS biology 248 25901609
2016 Genomic epidemiology of artemisinin resistant malaria. eLife 246 26943619
2016 Artemisinin Action and Resistance in Plasmodium falciparum. Trends in parasitology 239 27289273
2019 Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments-a WWARN individual patient data meta-analysis. BMC medicine 237 30651111
2017 A genetic system to study Plasmodium falciparum protein function. Nature methods 228 28288121
2020 Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria. Annual review of microbiology 221 32905757
2023 Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda. The New England journal of medicine 220 37611122
2016 Artemisinin-Resistant Plasmodium falciparum Malaria. Microbiology spectrum 212 27337450
2015 Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. The Lancet. Infectious diseases 205 25877962
2014 K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. The Journal of infectious diseases 200 25367300
2016 The clinical impact of artemisinin resistance in Southeast Asia and the potential for future spread. FEMS microbiology reviews 171 27613271
2021 Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda. The Journal of infectious diseases 167 33146722
2023 Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea. The New England journal of medicine 160 37754284
2018 Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study. The Lancet. Infectious diseases 156 29398391
2024 The emergence of artemisinin partial resistance in Africa: how do we respond? The Lancet. Infectious diseases 155 38552654
2023 Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia. Nature microbiology 151 37640962
2018 Effect of generalised access to early diagnosis and treatment and targeted mass drug administration on Plasmodium falciparum malaria in Eastern Myanmar: an observational study of a regional elimination programme. Lancet (London, England) 138 29703425
2018 Oxidative stress and protein damage responses mediate artemisinin resistance in malaria parasites. PLoS pathogens 137 29538461
2018 Mutations in Plasmodium falciparum actin-binding protein coronin confer reduced artemisinin susceptibility. Proceedings of the National Academy of Sciences of the United States of America 132 30420498
2022 Decreased susceptibility of Plasmodium falciparum to both dihydroartemisinin and lumefantrine in northern Uganda. Nature communications 131 36289202
2024 Emergence, transmission dynamics and mechanisms of artemisinin partial resistance in malaria parasites in Africa. Nature reviews. Microbiology 130 38321292
2019 Decreased K13 Abundance Reduces Hemoglobin Catabolism and Proteotoxic Stress, Underpinning Artemisinin Resistance. Cell reports 130 31775055
2021 Plasmodium falciparum K13 mutations in Africa and Asia impact artemisinin resistance and parasite fitness. eLife 129 34279219
2020 Local emergence in Amazonia of Plasmodium falciparum k13 C580Y mutants associated with in vitro artemisinin resistance. eLife 128 32394893
2021 Artemisinin-resistant K13 mutations rewire Plasmodium falciparum's intra-erythrocytic metabolic program to enhance survival. Nature communications 122 33483501
2018 Artemisinin-Resistant Plasmodium falciparum with High Survival Rates, Uganda, 2014-2016. Emerging infectious diseases 122 29553316
2015 A Single Mutation in K13 Predominates in Southern China and Is Associated With Delayed Clearance of Plasmodium falciparum Following Artemisinin Treatment. The Journal of infectious diseases 118 25910630
2015 Independent Emergence of the Plasmodium falciparum Kelch Propeller Domain Mutant Allele C580Y in Guyana. The Journal of infectious diseases 114 26690347
2014 Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children. PloS one 103 25144768
2017 Plasmodium falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro. mBio 101 28400526
2017 Artemisinin resistance without pfkelch13 mutations in Plasmodium falciparum isolates from Cambodia. Malaria journal 100 28494763
2015 Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes. Antimicrobial agents and chemotherapy 99 25779582
2019 Artemisinin Bioactivity and Resistance in Malaria Parasites. Trends in parasitology 93 31699532
2024 Evidence of artemisinin partial resistance in northwestern Tanzania: clinical and molecular markers of resistance. The Lancet. Infectious diseases 92 39159633
2020 Emergence of artemisinin-resistant Plasmodium falciparum with kelch13 C580Y mutations on the island of New Guinea. PLoS pathogens 89 33320907
2021 A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa. International journal for parasitology. Drugs and drug resistance 88 34146993
2021 Artemisinin and multidrug-resistant Plasmodium falciparum - a threat for malaria control and elimination. Current opinion in infectious diseases 88 34267045
2016 Population Parameters Underlying an Ongoing Soft Sweep in Southeast Asian Malaria Parasites. Molecular biology and evolution 88 28025270
2022 Plasmodium falciparum resistance to artemisinin-based combination therapies. Current opinion in microbiology 86 36007459
2018 Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance. Blood 82 29363540
2021 Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook. International journal for parasitology. Drugs and drug resistance 81 34090067
2014 Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009-2013). Malaria journal 81 25404021
2017 Multi-omics Based Identification of Specific Biochemical Changes Associated With PfKelch13-Mutant Artemisinin-Resistant Plasmodium falciparum. The Journal of infectious diseases 80 28368494
2017 Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort. Proceedings of the National Academy of Sciences of the United States of America 79 28289193
2016 Plasmodium falciparum: multifaceted resistance to artemisinins. Malaria journal 79 26955948
2015 Polymorphisms in the K13-propeller gene in artemisinin-susceptible Plasmodium falciparum parasites from Bougoula-Hameau and Bandiagara, Mali. The American journal of tropical medicine and hygiene 79 25918205
2020 Artemisinin-based combination therapy (ACT) and drug resistance molecular markers: A systematic review of clinical studies from two malaria endemic regions - India and sub-Saharan Africa. International journal for parasitology. Drugs and drug resistance 75 33556786
2017 Changing Antimalarial Drug Sensitivities in Uganda. Antimicrobial agents and chemotherapy 74 28923866
2015 Understanding artemisinin-resistant malaria: what a difference a year makes. Current opinion in infectious diseases 74 26237549
2020 K13, the Cytostome, and Artemisinin Resistance. Trends in parasitology 72 32359872
2015 Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012. Malaria journal 71 25927592
2021 Anti-malarial efficacy and resistance monitoring of artemether-lumefantrine and dihydroartemisinin-piperaquine shows inadequate efficacy in children in Burkina Faso, 2017-2018. Malaria journal 70 33468147
2015 A Unique Plasmodium falciparum K13 Gene Mutation in Northwest Ethiopia. The American journal of tropical medicine and hygiene 68 26483118
2021 Increase in Kelch 13 Polymorphisms in Plasmodium falciparum, Southern Rwanda. Emerging infectious diseases 67 33350925
2020 Insights into the intracellular localization, protein associations and artemisinin resistance properties of Plasmodium falciparum K13. PLoS pathogens 67 32310999
2019 Changing Molecular Markers of Antimalarial Drug Sensitivity across Uganda. Antimicrobial agents and chemotherapy 67 30559133
2016 Artemisinin Resistance-Associated K13 Polymorphisms of Plasmodium falciparum in Southern Rwanda, 2010-2015. The American journal of tropical medicine and hygiene 67 27573632
2020 Role of Plasmodium falciparum Kelch 13 Protein Mutations in P. falciparum Populations from Northeastern Myanmar in Mediating Artemisinin Resistance. mBio 66 32098812
2019 Novel pfkelch13 Gene Polymorphism Associates With Artemisinin Resistance in Eastern India. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 62 30535043
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
2021 Continued Low Efficacy of Artemether-Lumefantrine in Angola in 2019. Antimicrobial agents and chemotherapy 61 33168604
2018 Efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola, 2017. Malaria journal 60 29615039
2018 Drug-Resistant Polymorphisms and Copy Numbers in Plasmodium falciparum, Mozambique, 2015. Emerging infectious diseases 59 29260689
2020 Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review. The Lancet. Infectious diseases 58 33125913
2015 Surveillance of artemisinin resistance in Plasmodium falciparum in India using the kelch13 molecular marker. Antimicrobial agents and chemotherapy 58 25691626
2026 Artemisinin Partial Resistance Mutations in Zanzibar and Tanzania Suggest Regional Spread and African Origins, 2023. The Journal of infectious diseases 8 40802860
2026 Novel Pfk13 and Pfubp1 genotypes in African Plasmodium falciparum isolates exhibiting reduced susceptibility to the antimalarials artemisinin and lumefantrine. mBio 3 41738765
2026 National genomic profiling of Plasmodium falciparum antimalarial resistance in Zambian children participating in the 2018 malaria indicator survey. Scientific reports 3 42062354
2026 Chloroquine resistance transporter drives divergent multi-locus drug resistance genetic backgrounds and susceptibility in Gambian Plasmodium falciparum. Journal of global antimicrobial resistance 2 41985582
2026 Molecular Surveillance of Malaria in Nigeria Reveals a Low Frequency of Antimalarial Resistance Markers and Clonal Expansion of Chloroquine-Sensitive Infections. Open forum infectious diseases 1 41550699
2026 The Global Landscape of Plasmodium falciparum Drug Resistance Markers, 2005-2025: A Systematic Review and Meta-Analysis. Pathogens (Basel, Switzerland) 1 41754431
2026 Functional assessment of prevalent kelch13 mutations reveals high-level artemisinin resistance potential in Bangladeshi Plasmodium falciparum. mBio 1 41841738
2026 Border Region Surveillance of Malaria Drug Resistance, Northern Burundi, 2023-2024. Emerging infectious diseases 1 41927306
2026 Malaria in Bangladesh, 2000-2025: Navigating the Headwinds From Control to Elimination. Health science reports 1 42022606
2026 Artemisinin partial resistance at a crossroads: evidence for continental variation in Plasmodium falciparum clearance phenotypes. The Lancet. Infectious diseases 1 42107390
2026 Evaluation of the effectiveness of artemether-lumefantrine and artesunate-pyronaridine each combined with single low-dose primaquine in adults with Plasmodium falciparum infection in Ethiopia: a phase 2/3, observer-masked, randomised, parallel-group trial. The Lancet. Microbe 1 42259352
2026 Artemisinin resistance threat in Central and West Africa needs holistic action. Journal of public health in Africa 0 41647602
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 Emerging Artemisinin Partial Resistance in Southern Africa. The American journal of tropical medicine and hygiene 0 41843934
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 Artemether-lumefantrine for the treatment of Plasmodium falciparum malaria in Laos: a therapeutic efficacy study coupled with genomic and in vitro phenotypic analyses. The Lancet. Microbe 0 42155493
2026 Updated mapping of Plasmodium falciparum kelch13 gene polymorphisms in Madagascar, 2024. The Journal of antimicrobial chemotherapy 0 42169509
2026 Plasmodium falciparum non-synonymous Kelch13 mutations mediating artemisinin resistance in East Africa: A systematic review and meta-analysis: 2014-2024. PloS one 0 42520053
2026 Efficacy of artemisinin derivatives and kelch13 mutations in Plasmodium falciparum: a systematic review and meta-analysis. Transactions of the Royal Society of Tropical Medicine and Hygiene 0 42529832
2026 Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda. Nature medicine 0 42608602