Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast

Moore, Catherine M., Wang, Jigang, Lin, Qingsong, Ferreira, Pedro, Avery, Mitchell A, Elokely, Khaled, Staines, Henry M and Krishna, Sanjeev 2022. Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast. Antimicrobial Agents and Chemotherapy. 66 (5) e02079-21. https://doi.org/10.1128/aac.02079-21

TitleSelective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast
TypeJournal article
AuthorsMoore, Catherine M., Wang, Jigang, Lin, Qingsong, Ferreira, Pedro, Avery, Mitchell A, Elokely, Khaled, Staines, Henry M and Krishna, Sanjeev
Abstract

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool. The validated drug target Plasmodium falciparum ATPase 6 (PfATP6) and a mammalian orthologue (sarco/endoplasmic reticulum calcium ATPase 1a [SERCA1a]) were functionally expressed in Saccharomyces cerevisiae, providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labeling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesized, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low-technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multitargeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility.

Article numbere02079-21
JournalAntimicrobial Agents and Chemotherapy
Journal citation66 (5)
ISSN0066-4804
Year2022
PublisherAmerican Society for Microbiology
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1128/aac.02079-21
Web address (URL)https://europepmc.org/articles/PMC9112895
Publication dates
Published25 Apr 2022
Published13 Mar 2022

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