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Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance
- Source :
- Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, 2022, 66 (1), pp.e01320-21. ⟨10.1128/AAC.01320-21⟩
- Publication Year :
- 2022
- Publisher :
- American Society for Microbiology, 2022.
-
Abstract
- International audience; Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 (pfk13) gene. Here, we carried out in vitro selection over a 1-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.
- Subjects :
- medicine.medical_treatment
Plasmodium falciparum
Drug Resistance
Protozoan Proteins
Dihydroartemisinin
medicine.disease_cause
Epidemiology and Surveillance
Antimalarials
parasitic diseases
medicine
Coding region
CRISPR
[CHIM.COOR]Chemical Sciences/Coordination chemistry
Pharmacology (medical)
Artemisinin
BTB/POZ domain
Gene
Pharmacology
Mutation
biology
K13 mutation
[CHIM.COOR] Chemical Sciences/Coordination chemistry
Editor's Pick
biology.organism_classification
Virology
Artemisinins
Malaria
Infectious Diseases
Artemisinin resistance
BTB-POZ Domain
medicine.drug
Subjects
Details
- ISSN :
- 10986596 and 00664804
- Volume :
- 66
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy
- Accession number :
- edsair.doi.dedup.....aa70ff64915a7d8f74890e13f65a4174