TY - JOUR
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.
N1 - Funding 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank the Canberra branch of the Australian Red Cross Blood Service for providing red blood cells. We are also grateful to Marcin Adamski (ANU) for assistance with optimising PlaTyPus. We acknowledge the Monash Biomedical Proteomics Facility, Monash University, for the provision of instrumentation, training and technical support.
Publisher Copyright:
© 2018 Tjhin et al.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85046459963
U2 - 10.1371/journal.ppat.1006918
DO - 10.1371/journal.ppat.1006918
M3 - Article
C2 - 29614109
AN - SCOPUS:85046459963
SN - 1553-7366
VL - 14
JO - PLoS Pathogens
JF - PLoS Pathogens
IS - 4
M1 - e1006918
ER -