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

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

Author information

1
Research School of Biology, The Australian National University, Canberra, Australia.
2
Department of Chemistry, University of Glasgow, Glasgow, United Kingdom.
3
Department of Chemistry, McGill University, Montreal, Quebec, Canada.
4
Department of Biochemistry, Stellenbosch University, Matieland, South Africa.
5
Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
6
Department of Chemistry, Xi'an Jiaotong-Liverpool University, Suzhou, China.
7
Medical School, The Australian National University, Canberra, Australia.

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.

PMID:
29614109
PMCID:
PMC5882169
DOI:
10.1371/journal.ppat.1006918
[Indexed for MEDLINE]
Free PMC Article

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