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.
Highlights
Malaria is an important human parasitic disease that continues to threaten the lives of ~50% of the world’s population[1]
Since α-PanAm is an analog of pantothenic acid (PA), we examined its activity and with 10% dimethyl sulfoxide (DMSO)/PBS for the other group on days 2, 3 and 4 after parasite infection confirms inhibition of parasite blood stage growth caused by the drug treatment (Tx)
We describe a new method for synthesis of α-PanAm, and provide evidence that it is a potent inhibitor of intraerythrocytic P. falciparum development
Summary
Malaria is an important human parasitic disease that continues to threaten the lives of ~50% of the world’s population[1]. Pantothenic acid (vitamin B5), which serves as a precursor for the synthesis of Coenzyme A (CoA), has been shown to play a critical role in parasite metabolism and survival within human erythrocytes[5,8,13]. In yeast, this activity is encoded by the CAB1 gene and catalyzes the phosphorylation of pantothenate either transported from the yeast environment via the pantothenate transporter Fen2p or synthesized endogenously from β-alanine by the pantothenate synthase Pan6p16. Parasite stages were monitored by light microscopy after Giemsa staining
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