Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation

Selina Bopp, Charisse Flerida A. Pasaje, Robert L. Summers, Pamela Magistrado-Coxen, Kyra A. Schindler, Victoriano Corpas-Lopez, Tomas Yeo, Sachel Mok, Sumanta Dey, Sebastian Smick, Armiyaw S. Nasamu, Allison R. Demas, Rachel Milne, Natalie Wiedemar, Victoria Corey, Maria De Gracia Gomez-Lorenzo, Virginia Franco, Angela M. Early, Amanda K. Lukens, Danny Milner, Jeremy Furtado, Francisco-Javier Gamo, Elizabeth A. Winzeler, Sarah K. Volkman, Maëlle Duffey, Benoît Laleu, David A. Fidock, Susan Wyllie, Jacquin C. Niles & Dyann F. Wirth

Nat Commun 14, 1455 (2023). https://doi.org/10.1038/s41467-023-36921-2


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.