1. Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.
- Author
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Bopp, Selina, Pasaje, Charisse, Summers, Robert, Magistrado-Coxen, Pamela, Schindler, Kyra, Corpas-Lopez, Victoriano, Yeo, Tomas, Mok, Sachel, Dey, Sumanta, Smick, Sebastian, Nasamu, Armiyaw, Demas, Allison, Milne, Rachel, Wiedemar, Natalie, Corey, Victoria, Gomez-Lorenzo, Maria, Franco, Virginia, Early, Angela, Lukens, Amanda, Milner, Danny, Furtado, Jeremy, Gamo, Francisco-Javier, Winzeler, Elizabeth, Volkman, Sarah, Duffey, Maëlle, Laleu, Benoît, Fidock, David, Wyllie, Susan, Niles, Jacquin, and Wirth, Dyann
- Subjects
Humans ,Plasmodium falciparum ,Malaria ,Falciparum ,Antimalarials ,Mutation ,Ligases - Abstract
Identifying how small molecules act to kill malaria parasites can lead to new chemically validated targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability.
- Published
- 2023