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

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dc.contributor.authorTjhin, Erick T.en_ZA
dc.contributor.authorSpry, Christinaen_ZA
dc.contributor.authorSewell, Alan L.en_ZA
dc.contributor.authorHoegl, Annabelleen_ZA
dc.contributor.authorBarnard, Leanneen_ZA
dc.contributor.authorSexton, Anna E.en_ZA
dc.contributor.authorSiddiqui, Ghizalen_ZA
dc.contributor.authorHowieson, Vanessa M.en_ZA
dc.contributor.authorMaier, Alexander G.en_ZA
dc.contributor.authorCreek, Darren J.en_ZA
dc.contributor.authorStrauss, Ericken_ZA
dc.contributor.authorMarquez, Rodolfoen_ZA
dc.contributor.authorAuclair, Karinaen_ZA
dc.contributor.authorSaliba, Kevin J.en_ZA
dc.contributor.editorPhillips, Margaret A.en_ZA
dc.date.accessioned2019-10-14T14:02:19Z
dc.date.available2019-10-14T14:02:19Z
dc.date.issued2018-04-03
dc.descriptionCITATION: Tjhin, E. T. et al. 2018. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. PLoS Pathogens, 14(4):e1006918, doi:10.1371/journal.ppat.1006918.en_ZA
dc.descriptionThe original publication is available at https://journals.plos.org/plospathogensen_ZA
dc.description.abstractThe 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_ZA
dc.description.sponsorshipNational Health and Medical Research Council (NHMRC) of Australia
dc.description.sponsorshipCanadian Institute of Health Research (CIHR)
dc.description.sponsorshipNational Health and Medical Research Council (NHMRC)en_ZA
dc.description.sponsorshipCanadian Institute of Health Research (CIHR)en_ZA
dc.description.sponsorshipResearch Training Program scholarship (Australian Government)en_ZA
dc.description.sponsorshipNHMRC Overseas Biomedical Fellowshipen_ZA
dc.description.sponsorshipCIHRen_ZA
dc.description.versionPublisher's versionen_ZA
dc.format.extent30 pages : illustrationsen_ZA
dc.identifier.citationTjhin, E. T. et al. 2018. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. PLoS Pathogens, 14(4):e1006918, doi:10.1371/journal.ppat.1006918.en_ZA
dc.identifier.issn1553-7374 (online)
dc.identifier.orciddoi:10.1371/journal.ppat.1006918
dc.identifier.urihttp://hdl.handle.net/10019.1/106638
dc.language.isoen_ZAen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.rights.holderAuthors retain copyrighten_ZA
dc.subjectPlasmodium falciparumen_ZA
dc.subjectCoenzyme A (CoA) biosynthetic pathwayen_ZA
dc.subjectAntiplasmodial pantothenate analoguesen_ZA
dc.subjectMalaria parasitesen_ZA
dc.subjectAntimetabolitesen_ZA
dc.titleMutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analoguesen_ZA
dc.typeArticleen_ZA
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