Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

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. (2018-04-03)

CITATION: Tjhin, E. T. et al. 2018. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. PLoS Pathogens, 14(4):e1006918, doi:10.1371/journal.ppat.1006918.

The original publication is available at https://journals.plos.org/plospathogens

Article

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.

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