The antimalarial activity of the pantothenamide α-PanAm is via inhibition of pantothenate phosphorylation

Scientific Reports
Joy E ChiuChoukri Ben Mamoun

Abstract

The biosynthesis of the major acyl carrier Coenzyme A from pantothenic acid (PA) is critical for survival of Plasmodium falciparum within human erythrocytes. Accordingly, a PA analog α-PanAm showed potent activity against blood stage parasites in vitro; however, its efficacy in vivo and its mode of action remain unknown. We developed a new synthesis route for α-PanAm and showed that the compound is highly effective against blood stages of drug-sensitive and -resistant P. falciparum strains, inhibits development of P. berghei in hepatocytes, and at doses up to 100 mg/kg also inhibits blood stage development of P. chabaudi in mice. We used yeast and its pantothenate kinase Cab1 as models to characterize mode of action of α-PanAm and found that α-PanAm inhibits yeast growth in a PA-dependent manner, and its potency increases dramatically in a yeast mutant with defective pantothenate kinase activity. Biochemical analyses using 14C-PA as a substrate demonstrated that α-PanAm is a competitive inhibitor of Cab1. Interestingly, biochemical and mass spectrometry analyses also showed that the compound is phosphorylated by Cab1. Together, these data suggest that α-PanAm exerts its antimicrobial activity by direct competition with the natu...Continue Reading

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Citations

Sep 20, 2019·Science Translational Medicine·Joost SchalkwijkKoen J Dechering
Aug 14, 2019·Archives of Biochemistry and Biophysics·Dustin Duncan, Karine Auclair
Dec 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Romain MustièreNicolas Primas
Jul 30, 2021·PLoS Pathogens·Erick T TjhinKevin J Saliba

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Methods Mentioned

BETA
NMR
light microscopy
immunoprecipitation
column chromatography
Assay
fluorescence microscopy
scintillation spectrometry
gel filtration
Kinase

Software Mentioned

GraphPad Prism
Excel
Prism

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