Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast
Genre
Journal articleDate
2022-04-25Author
Moore, Catherine M.Wang, Jigang
Lin, Qingsong
Ferreira, Pedro
Avery, Mitchell A.
Elokely, Khaled

Staines, Henry M.
Krishna, Sanjeev
Group
Institute for Computational Molecular Science (Temple University)Department
ChemistrySubject
Saccharomyces cerevisiaeAntimalarial agents
Drug discovery
Drugresistance mechanisms
Drug screening
Mechanisms of action
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http://hdl.handle.net/20.500.12613/8150
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https://doi.org/10.1128/aac.02079-21Abstract
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.Citation to related work
American Society for MicrobiologyHas part
Antimicrobial Agents and Chemotherapy, Vol. 66, No. 5ADA compliance
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http://dx.doi.org/10.34944/dspace/8122