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

  • Journal Article
  • Research Support, Non-U.S. Gov't

Nature communications, Volume: 14, Issue: 1
March 16, 2023
Selina Bopp S, Charisse Flerida A Pasaje CFA, Robert L Summers RL, Pamela Magistrado-Coxen P, Kyra A Schindler KA, Victoriano Corpas-Lopez V, Tomas Yeo T, Sachel Mok S, Sumanta Dey S, Sebastian Smick S, Armiyaw S Nasamu AS, Allison R Demas AR, Rachel Milne R, Natalie Wiedemar N, Victoria Corey V, Maria De Gracia Gomez-Lorenzo MG, Virginia Franco V, Angela M Early AM, Amanda K Lukens AK, Danny Milner D, Jeremy Furtado J, Francisco-Javier Gamo FJ, Elizabeth A Winzeler EA, Sarah K Volkman SK, Maëlle Duffey M, Benoît Laleu B, David A Fidock DA, Susan Wyllie S, Jacquin C Niles JC, Dyann F Wirth DF

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.

Courtesy of the U.S. National Library of Medicine