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Structural and functional studies of histidine biosynthesis in Acanthamoeba spp. demonstrates a novel molecular arrangement and target for antimicrobials

DOI: 10.1371/journal.pone.0198827 DOI Help

Authors: Christopher A. Rice (University of West of Scotland; University of Strathclyde) , Sara J. Campbell (University of West of Scotland) , Claudine Bisson (University of Sheffield) , Hayley J. Owen (University of Sheffield) , Svetlana E. Sedelnikova (University of Sheffield) , Patrick J. Baker (University of Sheffield) , David W. Rice (University of Sheffield) , Fiona L. Henriquez (University of West of Scotland) , Craig W. Roberts (University of Strathclyde)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos One , VOL 13

State: Published (Approved)
Published: July 2018
Diamond Proposal Number(s): 7423

Open Access Open Access

Abstract: Acanthamoeba is normally free-living, but sometimes facultative and occasionally opportunistic parasites. Current therapies are, by necessity, arduous and yet poorly effective due to their inabilities to kill cyst stages or in some cases to actually induce encystation. Acanthamoeba can therefore survive as cysts and cause disease recurrence. Herein, in pursuit of better therapies and to understand the biochemistry of this understudied organism, we characterize its histidine biosynthesis pathway and explore the potential of targeting this with antimicrobials. We demonstrate that Acanthamoeba is a histidine autotroph, but with the ability to scavenge preformed histidine. It is able to grow in defined media lacking this amino acid, but is inhibited by 3-amino-1,2,4-triazole (3AT) that targets Imidazoleglycerol-Phosphate Dehydratase (IGPD) the rate limiting step of histidine biosynthesis. The structure of Acanthamoeba IGPD has also been determined in complex with 2-hydroxy-3-(1,2,4-triazol-1-yl) propylphosphonate [(R)-C348], a recently described novel inhibitor of Arabidopsis thaliana IGPD. This compound inhibited the growth of four Acanthamoeba species, having a 50% inhibitory concentration (IC50) ranging from 250–526 nM. This effect could be ablated by the addition of 1 mM exogenous free histidine, but importantly not by physiological concentrations found in mammalian tissues. The ability of 3AT and (R)-C348 to restrict the growth of four strains of Acanthamoeba spp. including a recently isolated clinical strain, while not inducing encystment, demonstrates the potential therapeutic utility of targeting the histidine biosynthesis pathway in Acanthamoeba.

Journal Keywords: Acanthamoeba; Histidine; Biosynthesis; Multiple alignment calculation; Sequence alignment; Arabidopsis thaliana; Polymerase chain reaction; Trophozoites

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Documents:
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