TY - JOUR
T1 - Potent acyl-CoA synthetase 10 inhibitors kill Plasmodium falciparum by disrupting triglyceride formation
AU - Bopp, Selina
AU - Pasaje, Charisse Flerida A.
AU - Summers, Robert L.
AU - Magistrado-Coxen, Pamela
AU - Schindler, Kyra A.
AU - Corpas-Lopez, Victoriano
AU - Yeo, Tomas
AU - Mok, Sachel
AU - Dey, Sumanta
AU - Smick, Sebastian
AU - Nasamu, Armiyaw S.
AU - Demas, Allison R.
AU - Milne, Rachel
AU - Wiedemar, Natalie
AU - Corey, Victoria
AU - Gomez-Lorenzo, Maria De Gracia
AU - Franco, Virginia
AU - Early, Angela M.
AU - Lukens, Amanda K.
AU - Milner, Danny
AU - Furtado, Jeremy
AU - Gamo, Francisco Javier
AU - Winzeler, Elizabeth A.
AU - Volkman, Sarah K.
AU - Duffey, Maëlle
AU - Laleu, Benoît
AU - Fidock, David A.
AU - Wyllie, Susan
AU - Niles, Jacquin C.
AU - Wirth, Dyann F.
N1 - Funding Information:
Bill and Melinda Gates Foundation grant OPP1156051 to DFW and grant OPP1054480 to EAW. Medicines for Malaria Venture (MMV08/0015) and NIH (R37 AI050234) to DAF.
Copyright:
© 2023, The Author(s).
PY - 2023/3/16
Y1 - 2023/3/16
N2 - 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.
AB - 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.
KW - Malaria
KW - Parasite biology
KW - Pathogens
UR - http://www.scopus.com/inward/record.url?scp=85150313946&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-36921-2
DO - 10.1038/s41467-023-36921-2
M3 - Article
C2 - 36927839
AN - SCOPUS:85150313946
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 1455
ER -
