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- Title
Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.
- Authors
Bopp, Selina; Pasaje, Charisse Flerida A.; Summers, Robert L.; Magistrado-Coxen, Pamela; Schindler, Kyra A.; Corpas-Lopez, Victoriano; Yeo, Tomas; Mok, Sachel; Dey, Sumanta; Smick, Sebastian; Nasamu, Armiyaw S.; Demas, Allison R.; Milne, Rachel; Wiedemar, Natalie; Corey, Victoria; Gomez-Lorenzo, Maria De Gracia; Franco, Virginia; Early, Angela M.; Lukens, Amanda K.; Milner, Danny
- 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. Drug resistance to current antimalarials is rising and new drugs and targets are urgently needed. Here the authors identify Plasmodium falciparum acyl-CoA synthetase 10 as a new target whose inhibition leads to a decrease in triacylglycerols.
- Subjects
PLASMODIUM falciparum; ACYL coenzyme A; SMALL molecules; BLOOD parasites; PLASMODIUM; ACYLTRANSFERASES; TRANSFER RNA
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-36921-2