Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes.

Abstract

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.

• Authors: Serena Pulcini, Henry M Staines, Jon K Pittman, Ksenija Slavic, Christian Doerig, Jean Halbert, Rita Tewari, Falgun Shah, Mitchell A Avery, Richard K Haynes, Sanjeev Krishna
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 208 Issue 3 Pg. 468-78 (Aug 01 2013) ISSN: 1537-6613 [Electronic] United States
• PMID: 23599312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP6 protein, Plasmodium falciparum
• Antimalarials
• Artemisinins
• artemisinin
• Calcium-Transporting ATPases

Topics

• Antimalarials (pharmacology)
• Artemisinins (pharmacology)
• Calcium-Transporting ATPases (genetics)
• Drug Resistance
• Gene Expression
• Humans
• Parasitic Sensitivity Tests (methods)
• Plasmodium falciparum (genetics)
• Polymorphism, Genetic
• Saccharomyces cerevisiae (drug effects, genetics)