title: Artemisinins act through at least two targets in a yeast model.
abstract: Artemisinin and related compounds are potent and widely used antimalarial drugs but their biochemical mode of action is not clear. There is strong evidence that ATP-dependent calcium transporters are a key target in the malarial parasite. However, work using Saccharomyces cerevisiae suggests that disruption of mitochondrial function is critical in the cell killing activity of these compounds. Here it is shown that, in the absence of reducing agents, artemisinin and artesunate targeted the S. cerevisiae calcium channels Pmr1p and Pmc1p. Both compounds affected the growth of yeast on fermentable and nonfermentable media. This growth inhibition was not seen in a yeast strain in which the genes encoding both calcium channels were deleted. In the presence of reducing agents, which break the endoperoxide bridge in the drugs, growth inhibition was only observed in nonfermentable media. This inhibition could be partially relieved by the addition of a free radical scavenger. These results suggest that the drugs have two biochemical modes of action - one acting by specific binding to calcium channels and one involving free radical production in the mitochondria.
authors.affiliation: School of Biological Sciences, Medical Biology Centre, Queen's University Belfast, Belfast, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Moore
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hoey
authors.forename: Alan
authors.initials: A
authors.lastname: Trudgett
authors.forename: David J
authors.initials: DJ
authors.lastname: Timson
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology; D037621:Artemisinins / Q000494:pharmacology*; D000077332:Artesunate; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D007783:Lactones / Q000494:pharmacology*; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D037621:Artemisinins; D007783:Lactones; D018832:Molecular Chaperones; C085484:PMC1 protein, S cerevisiae; C101767:SSC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000077332:Artesunate; D053499:Plasma Membrane Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; C075875:artemisin