ArticleMalaria journal2013
Artemisinin resistance in rodent malaria--mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking.
Article in Malaria journal, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 65 citations in OpenAlex.
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- Multiplex long-amplicon sequencing for comprehensive molecular surveillance of Plasmodium falciparum resistance to artemisinin and partner drugs in artemisinin-based combination therapies (ACTs).Parasites & vectors · 2025Article
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- Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance.Nature communications · 2024Article
- Whole genome sequencing identifies novel mutations in malaria parasites resistant to artesunate (ATN) and to ATN + mefloquine combination.Frontiers in cellular and infection microbiology · 2024Article
- Chemogenomic Profiling of a Plasmodium falciparum Transposon Mutant Library Reveals Shared Effects of Dihydroartemisinin and Bortezomib on Lipid Metabolism and Exported Proteins.Microbiology spectrum · 2023Article
- Stable endocytic structures navigate the complex pellicle of apicomplexan parasites.Nature communications · 2023Article
- Genetic mapping of determinants in drug resistance, virulence, disease susceptibility, and interaction of host-rodent malaria parasites.Parasitology international · 2022Review
- Antiplasmodial Cyclodecapeptides from Tyrothricin Share a Target with Chloroquine.Antibiotics (Basel, Switzerland) · 2022Article
- Current status of experimental models for the study of malaria.Parasitology · 2022Review
- Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.International journal for parasitology. Drugs and drug resistance · 2021Article
- Characterization ofAntimicrobial agents and chemotherapy · 2021Article
- Artemisinin susceptibility in the malaria parasite Plasmodium falciparum: propellers, adaptor proteins and the need for cellular healing.FEMS microbiology reviews · 2021Review
- Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility.Nature communications · 2020Article
- Article
- Experimentally Engineered Mutations in a Ubiquitin Hydrolase, UBP-1, ModulateAntimicrobial agents and chemotherapy · 2020Article
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Authors and funding
12 authors at 5 institutions in 5 countries.
Funding
Abstract
backgroundThe control of malaria, caused by Plasmodium falciparum, is hampered by the relentless evolution of drug resistance. Because artemisinin derivatives are now used in the most effective anti-malarial therapy, resistance to artemisinin would be catastrophic. Indeed, studies suggest that artemisinin resistance has already appeared in natural infections. Understanding the mechanisms of resistance would help to prolong the effective lifetime of these drugs. Genetic markers of resistance are therefore required urgently. Previously, a mutation in a de-ubiquitinating enzyme was shown to confer artemisinin resistance in the rodent malaria parasite Plasmodium chabaudi.
methodsHere, for a mutant P. chabaudi malaria parasite and its immediate progenitor, the in vivo artemisinin resistance phenotypes and the mutations arising using Illumina whole-genome re-sequencing were compared.
resultsAn increased artemisinin resistance phenotype is accompanied by one non-synonymous substitution. The mutated gene encodes the μ-chain of the AP2 adaptor complex, a component of the endocytic machinery. Homology models indicate that the mutated residue interacts with a cargo recognition sequence. In natural infections of the human malaria parasite P. falciparum, 12 polymorphisms (nine SNPs and three indels) were identified in the orthologous gene.
conclusionAn increased artemisinin-resistant phenotype occurs along with a mutation in a functional element of the AP2 adaptor protein complex. This suggests that endocytosis and trafficking of membrane proteins may be involved, generating new insights into possible mechanisms of resistance. The genotypes of this adaptor protein can be evaluated for its role in artemisinin responses in human infections of P. falciparum.
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