Expression in Yeast Links Field Polymorphisms in PfATP6 to in Vitro Artemisinin Resistance and Identifies New Inhibitor Classes
| Autor: | Rita Tewari, Henry M. Staines, Falgun Shah, Ksenija Slavic, Jon K. Pittman, Jean Halbert, Christian Doerig, Mitchell A. Avery, Richard K. Haynes, Serena Pulcini, Sanjeev Krishna |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Artemisinins
SERCA Plasmodium falciparum malaria Gene Expression Calcium-Transporting ATPases Saccharomyces cerevisiae Drug resistance yeast Pharmacology medicine.disease_cause cyclopiazonic acid Antimalarials 03 medical and health sciences chemistry.chemical_compound Parasitic Sensitivity Tests parasitic diseases medicine Humans Immunology and Allergy thaperoxides Artemisinin 030304 developmental biology Genetics 0303 health sciences Mutation Polymorphism Genetic drug resistance biology 030306 microbiology desferioxamine biology.organism_classification Yeast PfATP6 3. Good health Infectious Diseases chemistry Cyclopiazonic acid medicine.drug |
| Zdroj: | Journal of Infectious Diseases; Vol 208 |
| ISSN: | 1537-6613 0022-1899 |
| Popis: | Background. The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance. Results. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition. Conclusions. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome. |
| Databáze: | OpenAIRE |
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