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Title: | Genetic modulators of Plasmodium falciparum parasites asexual fitness and resistance to clinical and preclinical compounds | Authors: | Hong, Davin | Keywords: | Science::Biological sciences::Microbiology::Drug Resistance Science::Biological sciences::Genetics |
Issue Date: | 2023 | Publisher: | Nanyang Technological University | Source: | Hong, D. (2023). Genetic modulators of Plasmodium falciparum parasites asexual fitness and resistance to clinical and preclinical compounds. Final Year Project (FYP), Nanyang Technological University, Singapore. https://hdl.handle.net/10356/167504 | Abstract: | Emergence of malarial Plasmodium falciparum KEL1/PLA1 co-lineage in Southeast Asia caused the failure of dihydroartemisin+piperaquine (DHA+PPQ). PfKelch (k13) C580Y mutation and plasmepsins 2/3 gene (pm2/3) amplification, markers of DHA and PPQ resistance respectively, are hallmarks of KEL1/PLA1 parasites such as RF7, while PPQ resistance marker, M343L mutation in pfcrt on a mutant pfcrt Dd2 background, also emerged. Interactions between pfcrt M343L mutation and multicopy pm2/3 to confer PPQ resistance and the impact of KEL1/PLA1 hallmarks on parasite asexual fitness has not been elucidated. By using CRISPR/Cas9 editing and limiting dilution cloning of RF7 parasite and its drug-sensitive NF54 cross progeny, we illustrate the importance of pfcrt M343L background in PPQ resistance with pm2/3 amplification augmenting the phenotype. M343L mutation, however, did not confer resistance to artemisinin partner drugs lumefantrine or mefloquine, while pm2/3 amplification augmented resistance phenotype to preclinical compound MMV675939. Drug-free long-term competitive fitness assays between RF7 clones revealed that multicopy pm2/3 on mutant k13 led to moderate parasite fitness defect. These results confirmed DHA+PPQ selects for pm2/3 amplification and mutant k13/pfcrt parasites, allowing RF7 to emerge, but poor fitness in absence of PPQ can deamplify pm2/3. Current parasite genotypes reinforced the appeal of artesunate+mefloquine as a DHA+PPQ replacement. | URI: | https://hdl.handle.net/10356/167504 | Schools: | School of Biological Sciences | Organisations: | Columbia University | Fulltext Permission: | restricted | Fulltext Availability: | With Fulltext |
Appears in Collections: | SBS Student Reports (FYP/IA/PA/PI) |
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Final Year Project Thesis Report.pdf Restricted Access | 2.07 MB | Adobe PDF | View/Open |
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