1. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues.
- Author
-
Tjhin ET, Spry C, Sewell AL, Hoegl A, Barnard L, Sexton AE, Siddiqui G, Howieson VM, Maier AG, Creek DJ, Strauss E, Marquez R, Auclair K, and Saliba KJ
- Subjects
- Animals, Coenzyme A biosynthesis, Erythrocytes parasitology, Malaria parasitology, Pantothenic Acid pharmacology, Parasitic Sensitivity Tests, Phosphorylation, Protozoan Proteins genetics, Antimalarials pharmacology, Drug Resistance, Malaria drug therapy, Mutation, Pantothenic Acid analogs & derivatives, Phosphotransferases (Alcohol Group Acceptor) genetics, Plasmodium falciparum drug effects
- 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
- Full Text
- View/download PDF