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Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation
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Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation
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Journal Article
Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation
2023
Overview
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
Pf
ACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and
Pf
ACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates
Pf
ACS10 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
Pf
ACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the
Pf
ACS11 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/44
/ 13/51
/ 45/23
/ 82/58
/ Antimalarials - pharmacology
/ Antimalarials - therapeutic use
/ Genomes
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Malaria, Falciparum - parasitology
/ Mutation
/ Plasmodium falciparum - metabolism
/ Proteins
/ Science
