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Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens

Andrew Warrilow, Josie Parker, Claire Price Orcid Logo, Nicola J. Rolley, W. David Nes, Diane Kelly, Steven Kelly Orcid Logo

International Journal of Antimicrobial Agents

Swansea University Authors: Andrew Warrilow, Josie Parker, Claire Price Orcid Logo, Diane Kelly, Steven Kelly Orcid Logo

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DOI (Published version): 10.1016/j.ijantimicag.2019.07.011

Abstract

We report here the first evaluation of isavuconazole for inhibition of A. fumigatus CYP51 and of sterol biosynthesis in the fungus. Voriconazole and isavuconazole both bound tightly to recombinant AfCYP51A and AfCYP51B isolated in E. coli membranes. CYP51 reconstitution assays confirmed AfCYP51A and...

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Published in: International Journal of Antimicrobial Agents
ISSN: 09248579
Published: 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa51096
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Voriconazole and isavuconazole both bound tightly to recombinant AfCYP51A and AfCYP51B isolated in E. coli membranes. CYP51 reconstitution assays confirmed AfCYP51A and AfCYP51B in addition to three AfCYP51A mutants (G54W, L98H and M220K) were strongly inhibited by both triazoles. Voriconazole bound relatively weakly to purified HsCYP51 unlike isavuconazole, which bound tightly. However, isavuconazole was a relatively poor inhibitor of HsCYP51 activity with an IC50 value of 25 &#x3BC;M which was 55- to 120-fold greater than those observed for the A. fumigatus CYP51 enzymes, albeit not as poor an inhibitor of HsCYP51 as voriconazole which gave an IC50 value of 112 &#x3BC;M. Sterol analysis of triazole-treated A. fumigatus Af293 cells confirmed isavuconazole and voriconazole both inhibited cellular CYP51 activity with the accumulation of 14-methylated sterol substrates and depletion of ergosterol levels. Isavuconazole elicited a stronger perturbation of the sterol composition in Af293 than voriconazole at 0.0125 &#x3BC;g ml-1 indicating increased potency. However, complementation studies in Saccharomyces cerevisiae using strains containing AfCYP51A and AfCYP51B indicated isavuconazole to be equally as effective at inhibiting CYP51 activity as voriconazole. These in vitro studies suggest isavuconazole is an effective alternative to voriconazole as an antifungal agent against the target CYP51 in Aspergillus fumigatus.</abstract><type>Journal Article</type><journal>International Journal of Antimicrobial Agents</journal><publisher/><issnPrint>09248579</issnPrint><keywords>Isavuconazole, CYP51, Aspergillus fumigatus</keywords><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-12-31</publishedDate><doi>10.1016/j.ijantimicag.2019.07.011</doi><url/><notes/><college>COLLEGE NANME</college><department>Medicine, Health and Life Science - Faculty</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>FGMHL</DepartmentCode><institution>Swansea University</institution><degreesponsorsfunders>WEFO/ ERDF BEACON project</degreesponsorsfunders><apcterm/><lastEdited>2019-08-15T15:52:14.3609464</lastEdited><Created>2019-07-16T14:35:44.1898574</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Andrew</firstname><surname>Warrilow</surname><order>1</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>2</order></author><author><firstname>Claire</firstname><surname>Price</surname><orcid>0000-0002-6045-4835</orcid><order>3</order></author><author><firstname>Nicola J.</firstname><surname>Rolley</surname><order>4</order></author><author><firstname>W. David</firstname><surname>Nes</surname><order>5</order></author><author><firstname>Diane</firstname><surname>Kelly</surname><order>6</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>7</order></author></authors><documents><document><filename>0051096-09082019123922.pdf</filename><originalFilename>51096.pdf</originalFilename><uploaded>2019-08-09T12:39:22.6270000</uploaded><type>Output</type><contentLength>662219</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><embargoDate>2020-07-13T00:00:00.0000000</embargoDate><documentNotes>Released under the terms of a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2019-08-15T15:52:14.3609464 v2 51096 2019-07-16 Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 9a4e4dfa37f4318c6fa67933d4fc9a17 0000-0002-6045-4835 Claire Price Claire Price true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2019-07-16 FGMHL We report here the first evaluation of isavuconazole for inhibition of A. fumigatus CYP51 and of sterol biosynthesis in the fungus. Voriconazole and isavuconazole both bound tightly to recombinant AfCYP51A and AfCYP51B isolated in E. coli membranes. CYP51 reconstitution assays confirmed AfCYP51A and AfCYP51B in addition to three AfCYP51A mutants (G54W, L98H and M220K) were strongly inhibited by both triazoles. Voriconazole bound relatively weakly to purified HsCYP51 unlike isavuconazole, which bound tightly. However, isavuconazole was a relatively poor inhibitor of HsCYP51 activity with an IC50 value of 25 μM which was 55- to 120-fold greater than those observed for the A. fumigatus CYP51 enzymes, albeit not as poor an inhibitor of HsCYP51 as voriconazole which gave an IC50 value of 112 μM. Sterol analysis of triazole-treated A. fumigatus Af293 cells confirmed isavuconazole and voriconazole both inhibited cellular CYP51 activity with the accumulation of 14-methylated sterol substrates and depletion of ergosterol levels. Isavuconazole elicited a stronger perturbation of the sterol composition in Af293 than voriconazole at 0.0125 μg ml-1 indicating increased potency. However, complementation studies in Saccharomyces cerevisiae using strains containing AfCYP51A and AfCYP51B indicated isavuconazole to be equally as effective at inhibiting CYP51 activity as voriconazole. These in vitro studies suggest isavuconazole is an effective alternative to voriconazole as an antifungal agent against the target CYP51 in Aspergillus fumigatus. Journal Article International Journal of Antimicrobial Agents 09248579 Isavuconazole, CYP51, Aspergillus fumigatus 31 12 2019 2019-12-31 10.1016/j.ijantimicag.2019.07.011 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University WEFO/ ERDF BEACON project 2019-08-15T15:52:14.3609464 2019-07-16T14:35:44.1898574 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Andrew Warrilow 1 Josie Parker 2 Claire Price 0000-0002-6045-4835 3 Nicola J. Rolley 4 W. David Nes 5 Diane Kelly 6 Steven Kelly 0000-0001-7991-5040 7 0051096-09082019123922.pdf 51096.pdf 2019-08-09T12:39:22.6270000 Output 662219 application/pdf Accepted Manuscript true 2020-07-13T00:00:00.0000000 Released under the terms of a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND). true eng
title Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
spellingShingle Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
Andrew Warrilow
Josie Parker
Claire Price
Diane Kelly
Steven Kelly
title_short Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
title_full Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
title_fullStr Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
title_full_unstemmed Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
title_sort Isavuconazole and voriconazole inhibition of sterol 14α-demethylases (CYP51) from Aspergillus fumigatus and Homo sapiens
author_id_str_mv f066e233e8d0136c9f547b86fa43747f
e563ed4e1c7db8d1e131fb78a5f8d0d5
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5ccf81e5d5beedf32ef8d7c3d7ac6c8c
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author_id_fullname_str_mv f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
9a4e4dfa37f4318c6fa67933d4fc9a17_***_Claire Price
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Andrew Warrilow
Josie Parker
Claire Price
Diane Kelly
Steven Kelly
author2 Andrew Warrilow
Josie Parker
Claire Price
Nicola J. Rolley
W. David Nes
Diane Kelly
Steven Kelly
format Journal article
container_title International Journal of Antimicrobial Agents
publishDate 2019
institution Swansea University
issn 09248579
doi_str_mv 10.1016/j.ijantimicag.2019.07.011
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description We report here the first evaluation of isavuconazole for inhibition of A. fumigatus CYP51 and of sterol biosynthesis in the fungus. Voriconazole and isavuconazole both bound tightly to recombinant AfCYP51A and AfCYP51B isolated in E. coli membranes. CYP51 reconstitution assays confirmed AfCYP51A and AfCYP51B in addition to three AfCYP51A mutants (G54W, L98H and M220K) were strongly inhibited by both triazoles. Voriconazole bound relatively weakly to purified HsCYP51 unlike isavuconazole, which bound tightly. However, isavuconazole was a relatively poor inhibitor of HsCYP51 activity with an IC50 value of 25 μM which was 55- to 120-fold greater than those observed for the A. fumigatus CYP51 enzymes, albeit not as poor an inhibitor of HsCYP51 as voriconazole which gave an IC50 value of 112 μM. Sterol analysis of triazole-treated A. fumigatus Af293 cells confirmed isavuconazole and voriconazole both inhibited cellular CYP51 activity with the accumulation of 14-methylated sterol substrates and depletion of ergosterol levels. Isavuconazole elicited a stronger perturbation of the sterol composition in Af293 than voriconazole at 0.0125 μg ml-1 indicating increased potency. However, complementation studies in Saccharomyces cerevisiae using strains containing AfCYP51A and AfCYP51B indicated isavuconazole to be equally as effective at inhibiting CYP51 activity as voriconazole. These in vitro studies suggest isavuconazole is an effective alternative to voriconazole as an antifungal agent against the target CYP51 in Aspergillus fumigatus.
published_date 2019-12-31T04:02:51Z
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score 11.016235

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