TY - JOUR T1 - Mutations in the pantothenate kinase of the malaria parasite <em>P. falciparum</em> confer resistance or hypersensitivity to diverse pantothenate analogues JF - bioRxiv DO - 10.1101/137182 SP - 137182 AU - Erick T. Tjhin AU - Christina Spry AU - Alan L. Sewell AU - Annabelle Hoegl AU - Leanne Barnard AU - Anna E. Sexton AU - Vanessa M. Howieson AU - Alexander G. Maier AU - Darren J. Creek AU - Erick Strauss AU - Rodolfo Marquez AU - Karine Auclair AU - Kevin J. Saliba Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/05/16/137182.abstract N2 - 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. ER -