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.
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; Andrew H Lee; Sarah H Shafik; Guillaume Bouyer; Catherine M Moore; Daniel A Daley; Matthew J Hoke; Lindsey M Altenhofen; Heather J Painter; Jianbing Mu; David J P Ferguson; Manuel Llinás; Rowena E Martin; David A Fidock; Roland A Cooper; Sanjeev Krishna Journal: Sci Rep Date: 2015-09-30 Impact factor: 4.379
Authors: Ksenija Slavic; Sanjeev Krishna; Aparajita Lahree; Guillaume Bouyer; Kirsten K Hanson; Iset Vera; Jon K Pittman; Henry M Staines; Maria M Mota Journal: Nat Commun Date: 2016-01-20 Impact factor: 14.919
Authors: Christian N Nguetse; Ayola Akim Adegnika; Tsiri Agbenyega; Bernhards R Ogutu; Sanjeev Krishna; Peter G Kremsner; Thirumalaisamy P Velavan Journal: Malar J Date: 2017-05-23 Impact factor: 2.979
Authors: Farrah A Fatih; Henry M Staines; Angela Siner; Mohammed Atique Ahmed; Lu Chan Woon; Erica M Pasini; Clemens Hm Kocken; Balbir Singh; Janet Cox-Singh; Sanjeev Krishna Journal: Malar J Date: 2013-11-19 Impact factor: 2.979