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

Autor: Erick T Tjhin, Christina Spry, Alan L Sewell, Annabelle Hoegl, Leanne Barnard, Anna E Sexton, Ghizal Siddiqui, Vanessa M Howieson, Alexander G Maier, Darren J Creek, Erick Strauss, Rodolfo Marquez, Karine Auclair, Kevin J Saliba
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: PLoS Pathogens, Vol 14, Iss 4, p e1006918 (2018)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1006918
Popis: 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.
Databáze: Directory of Open Access Journals
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