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

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) (PMID:29614109) (PMCID:PMC5882169)

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.

• Item Type: Articles
• Additional Information: Part of this work was funded by a grant from the National Health and Medical Research Council (NHMRC) of Australia to KJS and KA. (APP1129843), and a grant from the Canadian Institute of Health Research (CIHR) to KA. ETT was supported by a Research Training Program scholarship from the Australian Government. CS was funded by an NHMRC Overseas Biomedical Fellowship (1016357). CIHR provided a graduate scholarship to AH.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sewell, Mr Alan

Creator Roles

Sewell, A. L.: Resources, Validation

• Authors: Tjhin, E. T., Spry, C., Sewell, A. L., Hoegl, A., Barnard, L., Sexton, A. E., Siddiqui, G., Howieson, V. M., Maier, A. G., Creek, D. J., Strauss, E., Marquez, R., Auclair, K., and Saliba, K. J.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: PLoS Pathogens
• Publisher: Public Library of Science
• ISSN: 1553-7366
• ISSN (Online): 1553-7374
• Copyright Holders: Copyright © 2018 Tjhin et al.
• First Published: First published in PLoS Pathogens 14(4): e1006918
• Publisher Policy: Reproduced under a Creative Commons License