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

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 pantoth...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882169/
https://www.ncbi.nlm.nih.gov/pubmed/29614109
http://dx.doi.org/10.1371/journal.ppat.1006918
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author 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.
author_facet 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.
author_sort Tjhin, Erick T.
collection PubMed
description 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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spelling pubmed-58821692018-04-13 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. PLoS Pathog Research Article 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. Public Library of Science 2018-04-03 /pmc/articles/PMC5882169/ /pubmed/29614109 http://dx.doi.org/10.1371/journal.ppat.1006918 Text en © 2018 Tjhin et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
title Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
title_full Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
title_fullStr Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
title_full_unstemmed Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
title_short Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
title_sort mutations in the pantothenate kinase of plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882169/
https://www.ncbi.nlm.nih.gov/pubmed/29614109
http://dx.doi.org/10.1371/journal.ppat.1006918
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