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 MilnerJeremy 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 (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
24 Downloads (Pure)

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.

Original languageEnglish
Article number1455
Number of pages15
JournalNature Communications
Volume14
DOIs
Publication statusPublished - 16 Mar 2023

Keywords

  • Malaria
  • Parasite biology
  • Pathogens

ASJC Scopus subject areas

  • General
  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation'. Together they form a unique fingerprint.

Cite this