%0 Journal Article
%T Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
%A Alan L. Sewell
%A Alexander G. Maier
%A Anna E. Sexton
%A Annabelle Hoegl
%A Christina Spry
%A Darren J. Creek
%A Erick Strauss
%A Erick T. Tjhin
%A Ghizal Siddiqui
%A Karine Auclair
%A Kevin J. Saliba
%A Leanne Barnard
%A Rodolfo Marquez
%A Vanessa M. Howieson
%J -
%D 2018
%R 10.1371/journal.ppat.1006918
%X The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes
%K Phosphorylation
%K Cloning
%K Parasitic diseases
%K Plasmodium
%K Malarial parasites
%K Red blood cells
%K Enzyme inhibitors
%K Polymerase chain reaction
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006918