Pantothenamides are potent, on-target inhibitors of plasmodium falciparum growth when serum pantetheinase is inactivated
Date
2013-02
Authors
Spry, Christina
Macuamule, Cristiano
Lin, Zhiyang
Virga, Kristopher G.
Lee, Richard E.
Strauss, Erick
Saliba, Kevin J.
Journal Title
Journal ISSN
Volume Title
Publisher
PLoS
Abstract
Growth of the virulent human malaria parasite Plasmodium falciparum is dependent on an extracellular supply of
pantothenate (vitamin B5) and is susceptible to inhibition by pantothenate analogues that hinder pantothenate utilization.
In this study, on the hunt for pantothenate analogues with increased potency relative to those reported previously, we
screened a series of pantothenamides (amide analogues of pantothenate) against P. falciparum and show for the first time
that analogues of this type possess antiplasmodial activity. Although the active pantothenamides in this series exhibit only
modest potency under standard in vitro culture conditions, we show that the potency of pantothenamides is selectively
enhanced when the parasite culture medium is pre-incubated at 37uC for a prolonged period. We present evidence that this
finding is linked to the presence in Albumax II (a serum-substitute routinely used for in vitro cultivation of P. falciparum) of
pantetheinase activity: the activity of an enzyme that hydrolyzes the pantothenate metabolite pantetheine, for which
pantothenamides also serve as substrates. Pantetheinase activity, and thereby pantothenamide degradation, is reduced
following incubation of Albumax II-containing culture medium for a prolonged period at 37uC, revealing the true, submicromolar
potency of pantothenamides. Importantly we show that the potent antiplasmodial effect of pantothenamides is
attenuated with pantothenate, consistent with the compounds inhibiting parasite proliferation specifically by inhibiting
pantothenate and/or CoA utilization. Additionally, we show that the pantothenamides interact with P. falciparum
pantothenate kinase, the first enzyme involved in converting pantothenate to coenzyme A. This is the first demonstration of
on-target antiplasmodial pantothenate analogues with sub-micromolar potency, and highlights the potential of
pantetheinase-resistant pantothenamides as antimalarial agents.
Description
Please cite as follows: Spry, C. et al. 2013. Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When. PLoS ONE, 8(2): e54974, doi:10.1371/journal.pone.0054974.
The original publication is available at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054974
The original publication is available at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054974
Keywords
Pantothenamides, Malaria -- Prevention, Plasmodium falciparum, Drug resistance in microorganisms
Citation
Spry, C. et al. 2013. Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When. PLoS ONE, 8(2): e54974, doi:10.1371/journal.pone.0054974.