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

Erick T. Tjhin, Christina Spry, Alan L. Sewell, Annabelle Hoegl, Leanne Barnard, Anna E. Sexton, Ghizal Siddiqui, Vanessa M. Howieson, Alexander G. Maier, Darren J. Creek, Erick Strauss, Rodolfo Marquez, Karine Auclair, Kevin J. Saliba

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3 Citations (Scopus)

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.

Original languageEnglish
Article numbere1006918
Number of pages30
JournalPLoS Pathogens
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Cite this

Tjhin, Erick T. ; Spry, Christina ; Sewell, Alan L. ; Hoegl, Annabelle ; Barnard, Leanne ; Sexton, Anna E. ; Siddiqui, Ghizal ; Howieson, Vanessa M. ; Maier, Alexander G. ; Creek, Darren J. ; Strauss, Erick ; Marquez, Rodolfo ; Auclair, Karine ; Saliba, Kevin J. / Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. In: PLoS Pathogens. 2018 ; Vol. 14, No. 4.
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title = "Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues",
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.",
author = "Tjhin, {Erick T.} and Christina Spry and Sewell, {Alan L.} and Annabelle Hoegl and Leanne Barnard and Sexton, {Anna E.} and Ghizal Siddiqui and Howieson, {Vanessa M.} and Maier, {Alexander G.} and Creek, {Darren J.} and Erick Strauss and Rodolfo Marquez and Karine Auclair and Saliba, {Kevin J.}",
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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 2018, 'Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues', PLoS Pathogens, vol. 14, no. 4, e1006918. https://doi.org/10.1371/journal.ppat.1006918

Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. / Tjhin, Erick T.; Spry, Christina; Sewell, Alan L.; Hoegl, Annabelle; Barnard, Leanne; Sexton, Anna E.; Siddiqui, Ghizal; Howieson, Vanessa M.; Maier, Alexander G.; Creek, Darren J.; Strauss, Erick; Marquez, Rodolfo; Auclair, Karine; Saliba, Kevin J.

In: PLoS Pathogens, Vol. 14, No. 4, e1006918, 01.04.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

AU - Tjhin, Erick T.

AU - Spry, Christina

AU - Sewell, Alan L.

AU - Hoegl, Annabelle

AU - Barnard, Leanne

AU - Sexton, Anna E.

AU - Siddiqui, Ghizal

AU - Howieson, Vanessa M.

AU - Maier, Alexander G.

AU - Creek, Darren J.

AU - Strauss, Erick

AU - Marquez, Rodolfo

AU - Auclair, Karine

AU - Saliba, Kevin J.

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AB - 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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U2 - 10.1371/journal.ppat.1006918

DO - 10.1371/journal.ppat.1006918

M3 - Article

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JO - PLoS Pathogens

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