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

PLoS Pathog. 2018 Apr 3;14(4):e1006918. doi: 10.1371/journal.ppat.1006918. eCollection 2018 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / pharmacology*
  • Coenzyme A / biosynthesis
  • Drug Resistance*
  • Erythrocytes / parasitology
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Mutation*
  • Pantothenic Acid / analogs & derivatives*
  • Pantothenic Acid / pharmacology
  • Parasitic Sensitivity Tests
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Plasmodium falciparum / drug effects*
  • Protozoan Proteins / genetics

Substances

  • Antimalarials
  • CJ-15,801
  • Protozoan Proteins
  • Pantothenic Acid
  • Phosphotransferases (Alcohol Group Acceptor)
  • pantothenate kinase
  • Coenzyme A

Grant support

Part of this work was funded by a grant from the National Health and Medical Research Council (NHMRC) of Australia to KJS and KA. (APP1129843), and a grant from the Canadian Institute of Health Research (CIHR) to KA. ETT was supported by a Research Training Program scholarship from the Australian Government. CS was funded by an NHMRC Overseas Biomedical Fellowship (1016357). CIHR provided a graduate scholarship to AH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.