Browsing by Author "Creek, Darren J."

Now showing 1 - 1 of 1
  • Thumbnail Image
    Item
    Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
    (Public Library of Science, 2018-04-03) Tjhin, Erick T.; Spry, Christina; Sewell, Alan L.; Hoegl, Annabelle; Barnard, Leanne; Sexton, Anna E.; Siddiqui, Ghizal; Howieson, Vanessa M.; Maier, Alexander G.; Creek, Darren J.; Strauss, Erick; Marquez, Rodolfo; Auclair, Karina; Saliba, Kevin J.; Phillips, Margaret A.
    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.