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Sci Rep. 2017 Oct 27;7(1):14234. doi: 10.1038/s41598-017-14074-9.

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

Author information

1
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Basic Science Section, Department of Medicine, National Jewish Health, 1400 Jackson St, Denver, Colorado, 80206, USA.
3
Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, 70112, USA.
4
New England Discovery Partners, Branford, CT, USA.
5
Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. choukri.benmamoun@yale.edu.

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 natural substrate PA for phosphorylation by the pantothenate kinase.

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