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

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; Saliba, KJ

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

Spry, C Sewell, AL Hoegl, A Barnard, L Sexton, AE Siddiqui, G Howieson, VM Maier, AG Creek, DJ Strauss, E Marquez, R Auclair, K Saliba, KJ

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Publication Type:: Journal Article
Citation:: PLoS Pathogens, 2018, 14 (4)
Issue Date:: 2018-04-01

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Field	Value	Language
dc.contributor.author	Tjhin, ET https://orcid.org/0000-0003-1711-0815	en_US
dc.contributor.author	Spry, C	en_US
dc.contributor.author	Sewell, AL	en_US
dc.contributor.author	Hoegl, A	en_US
dc.contributor.author	Barnard, L	en_US
dc.contributor.author	Sexton, AE	en_US
dc.contributor.author	Siddiqui, G	en_US
dc.contributor.author	Howieson, VM	en_US
dc.contributor.author	Maier, AG	en_US
dc.contributor.author	Creek, DJ	en_US
dc.contributor.author	Strauss, E	en_US
dc.contributor.author	Marquez, R	en_US
dc.contributor.author	Auclair, K	en_US
dc.contributor.author	Saliba, KJ	en_US
dc.date.available	2018-02-01	en_US
dc.date.issued	2018-04-01	en_US
dc.identifier.citation	PLoS Pathogens, 2018, 14 (4)	en_US
dc.identifier.issn	1553-7366	en_US
dc.identifier.uri	http://hdl.handle.net/10453/130731
dc.description.abstract	© 2018 Tjhin et al. 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.	en_US
dc.relation.ispartof	PLoS Pathogens	en_US
dc.relation.isbasedon	10.1371/journal.ppat.1006918	en_US
dc.subject.classification	Virology	en_US
dc.subject.mesh	Erythrocytes	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Plasmodium falciparum	en_US
dc.subject.mesh	Malaria	en_US
dc.subject.mesh	Coenzyme A	en_US
dc.subject.mesh	Phosphotransferases (Alcohol Group Acceptor)	en_US
dc.subject.mesh	Pantothenic Acid	en_US
dc.subject.mesh	Protozoan Proteins	en_US
dc.subject.mesh	Antimalarials	en_US
dc.subject.mesh	Parasitic Sensitivity Tests	en_US
dc.subject.mesh	Phosphorylation	en_US
dc.subject.mesh	Drug Resistance	en_US
dc.subject.mesh	Mutation	en_US
dc.title	Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	14	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	1107 Immunology	en_US
utslib.for	1108 Medical Microbiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	14	en_US

Abstract:

© 2018 Tjhin et al. 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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http://hdl.handle.net/10453/130731