Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba

Abstract The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using...

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Autores principales:	Scott Thomson, Christopher A. Rice, Tong Zhang, RuAngelie Edrada-Ebel, Fiona L. Henriquez, Craig W. Roberts
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6aae8a6a857649b49c992ac7999b6f8f
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spelling	oai:doaj.org-article:6aae8a6a857649b49c992ac7999b6f8f2021-12-02T16:06:49ZCharacterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba10.1038/s41598-017-07495-z2045-2322https://doaj.org/article/6aae8a6a857649b49c992ac7999b6f8f2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07495-zhttps://doaj.org/toc/2045-2322Abstract The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14α-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production. Unlike previously reported, we find no evidence of 7-dehydrostigmasterol or any other phytosterol in Acanthamoeba. Of five azoles tested, we demonstrate that tioconazole and voriconazole have the greatest overall inhibition for all isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga tested. While miconazole and sulconazole have intermediate activity econazole is least effective. Through GCMS, we demonstrate that voriconazole inhibits 14α-demethylase as treatment inhibits the production of ergosterol, but results in the accumulation of the lanosterol substrate. These data provide the most complete description of sterol metabolism in Acanthamoeba, provide a putative framework for their further study and validate 14α-demethylase as the target for azoles in Acanthamoeba.Scott ThomsonChristopher A. RiceTong ZhangRuAngelie Edrada-EbelFiona L. HenriquezCraig W. RobertsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Scott Thomson Christopher A. Rice Tong Zhang RuAngelie Edrada-Ebel Fiona L. Henriquez Craig W. Roberts Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
description	Abstract The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14α-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production. Unlike previously reported, we find no evidence of 7-dehydrostigmasterol or any other phytosterol in Acanthamoeba. Of five azoles tested, we demonstrate that tioconazole and voriconazole have the greatest overall inhibition for all isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga tested. While miconazole and sulconazole have intermediate activity econazole is least effective. Through GCMS, we demonstrate that voriconazole inhibits 14α-demethylase as treatment inhibits the production of ergosterol, but results in the accumulation of the lanosterol substrate. These data provide the most complete description of sterol metabolism in Acanthamoeba, provide a putative framework for their further study and validate 14α-demethylase as the target for azoles in Acanthamoeba.
format	article
author	Scott Thomson Christopher A. Rice Tong Zhang RuAngelie Edrada-Ebel Fiona L. Henriquez Craig W. Roberts
author_facet	Scott Thomson Christopher A. Rice Tong Zhang RuAngelie Edrada-Ebel Fiona L. Henriquez Craig W. Roberts
author_sort	Scott Thomson
title	Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
title_short	Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
title_full	Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
title_fullStr	Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
title_full_unstemmed	Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba
title_sort	characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in acanthamoeba
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6aae8a6a857649b49c992ac7999b6f8f
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Characterisation of sterol biosynthesis and validation of 14α-demethylase as a drug target in Acanthamoeba

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