Nature communications · 2023
Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Bopp Selina, Pasaje Charisse Flerida A, Summers Robert L, Magistrado-Coxen Pamela, Schindler Kyra A, Corpas-Lopez Victoriano, Yeo Tomas, Mok Sachel, Dey Sumanta, Smick Sebastian, Nasamu Armiyaw S, Demas Allison R, Milne Rachel, Wiedemar Natalie, Corey Victoria, Gomez-Lorenzo Maria De Gracia, Franco Virginia, Early Angela M, Lukens Amanda K, Milner Danny, Furtado Jeremy, Gamo Francisco-Javier, Winzeler Elizabeth A, Volkman Sarah K, Duffey Maëlle, Laleu Benoît, Fidock David A, Wyllie Susan, Niles Jacquin C, Wirth Dyann F
Аннотация
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.