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

Nat Commun. 2023 Mar 16;14(1):1455. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials* / pharmacology
  • Antimalarials* / therapeutic use
  • Humans
  • Ligases / metabolism
  • Malaria, Falciparum* / drug therapy
  • Malaria, Falciparum* / parasitology
  • Mutation
  • Plasmodium falciparum / metabolism


  • Antimalarials
  • Ligases