1. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
- Author
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Tjhin, Erick, Spry, Christina, Sewell, Alan L, Hoegl, Annabelle, Barnard, Leanne, Sexton, Anna E, Siddiqui, Ghizal, Howieson, Vanessa, Maier, Alex, Creek, Darren J, Strauss, Erick, Marquez, Rodolfo, Auclair, Karine, Saliba, Kevin, Tjhin, Erick, Spry, Christina, Sewell, Alan L, Hoegl, Annabelle, Barnard, Leanne, Sexton, Anna E, Siddiqui, Ghizal, Howieson, Vanessa, Maier, Alex, Creek, Darren J, Strauss, Erick, Marquez, Rodolfo, Auclair, Karine, and Saliba, Kevin
- Abstract
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.
- Published
- 2018