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Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus

Josie Parker, M Merkamm, N. J Manning, D Pompon, Steven Kelly Orcid Logo, Diane Kelly

Antimicrobial Agents and Chemotherapy, Volume: 52, Issue: 10, Pages: 3597 - 3603

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo, Diane Kelly

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DOI (Published version): 10.1128/AAC.00517-08

Abstract

Inhibition of sterol-14α-demethylase, a cytochrome P450 (CYP51, Erg11p), is the mode of action of azole antifungal drugs, and with high frequencies of fungal infections new agents are required. New drugs that target fungal CYP51 should not inhibit human CYP51, although selective inhibitors...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2008
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URI: https://cronfa.swan.ac.uk/Record/cronfa6835
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2021-10-26T15:26:43.6761099</datestamp><bib-version>v2</bib-version><id>6835</id><entry>2012-01-25</entry><title>Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14&#xA0;alpha-Demethylase at the Homologous Locus</title><swanseaauthors><author><sid>e563ed4e1c7db8d1e131fb78a5f8d0d5</sid><firstname>Josie</firstname><surname>Parker</surname><name>Josie Parker</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>b17cebaf09b4d737b9378a3581e3de93</sid><ORCID>0000-0001-7991-5040</ORCID><firstname>Steven</firstname><surname>Kelly</surname><name>Steven Kelly</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>5ccf81e5d5beedf32ef8d7c3d7ac6c8c</sid><firstname>Diane</firstname><surname>Kelly</surname><name>Diane Kelly</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2012-01-25</date><deptcode>FGMHL</deptcode><abstract>Inhibition of sterol-14&amp;alpha;-demethylase, a cytochrome P450 (CYP51, Erg11p), is the mode of action of azole antifungal drugs, and with high frequencies of fungal infections new agents are required. New drugs that target fungal CYP51 should not inhibit human CYP51, although selective inhibitors of the human target are also of interest as anticholesterol agents. A strain of Saccharomyces cerevisiae that was humanized with respect to the amino acids encoded at the CYP51 (ERG11) yeast locus (BY4741:huCYP51) was produced. The strain was validated with respect to gene expression, protein localization, growth characteristics, and sterol content. The MIC was determined and compared to that for the wild-type parental strain (BY4741), using clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole. The humanized strain showed up to &amp;gt;1,000-fold-reduced susceptibility to the orally active azole drugs, while the topical agents showed no difference. Data from growth kinetic measurements substantiated this finding but also revealed reduced effectiveness against the humanized strain for the topical drugs. Cellular sterol profiles reflected the decreased susceptibility of BY4741:huCYP51 and showed a smaller depletion of ergosterol and accumulation of 14&amp;alpha;-methyl-ergosta-8, 24(28)-dien-3&amp;beta;-6&amp;alpha;-diol than the parental strain under the same treatment conditions. This strain provides a useful tool for initial specificity testing for new drugs targeting CYP51 and clearly differentiates azole antifungals in a side-by-side comparison.</abstract><type>Journal Article</type><journal>Antimicrobial Agents and Chemotherapy</journal><volume>52</volume><journalNumber>10</journalNumber><paginationStart>3597</paginationStart><paginationEnd>3603</paginationEnd><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0066-4804</issnPrint><issnElectronic>1098-6596</issnElectronic><keywords/><publishedDay>31</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2008</publishedYear><publishedDate>2008-10-31</publishedDate><doi>10.1128/AAC.00517-08</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><apcterm/><lastEdited>2021-10-26T15:26:43.6761099</lastEdited><Created>2012-01-25T14:15:44.3600000</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>Josie</firstname><surname>Parker</surname><order>1</order></author><author><firstname>M</firstname><surname>Merkamm</surname><order>2</order></author><author><firstname>N. J</firstname><surname>Manning</surname><order>3</order></author><author><firstname>D</firstname><surname>Pompon</surname><order>4</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>5</order></author><author><firstname>Diane</firstname><surname>Kelly</surname><order>6</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2021-10-26T15:26:43.6761099 v2 6835 2012-01-25 Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false 2012-01-25 FGMHL Inhibition of sterol-14&alpha;-demethylase, a cytochrome P450 (CYP51, Erg11p), is the mode of action of azole antifungal drugs, and with high frequencies of fungal infections new agents are required. New drugs that target fungal CYP51 should not inhibit human CYP51, although selective inhibitors of the human target are also of interest as anticholesterol agents. A strain of Saccharomyces cerevisiae that was humanized with respect to the amino acids encoded at the CYP51 (ERG11) yeast locus (BY4741:huCYP51) was produced. The strain was validated with respect to gene expression, protein localization, growth characteristics, and sterol content. The MIC was determined and compared to that for the wild-type parental strain (BY4741), using clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole. The humanized strain showed up to &gt;1,000-fold-reduced susceptibility to the orally active azole drugs, while the topical agents showed no difference. Data from growth kinetic measurements substantiated this finding but also revealed reduced effectiveness against the humanized strain for the topical drugs. Cellular sterol profiles reflected the decreased susceptibility of BY4741:huCYP51 and showed a smaller depletion of ergosterol and accumulation of 14&alpha;-methyl-ergosta-8, 24(28)-dien-3&beta;-6&alpha;-diol than the parental strain under the same treatment conditions. This strain provides a useful tool for initial specificity testing for new drugs targeting CYP51 and clearly differentiates azole antifungals in a side-by-side comparison. Journal Article Antimicrobial Agents and Chemotherapy 52 10 3597 3603 0066-4804 1098-6596 31 10 2008 2008-10-31 10.1128/AAC.00517-08 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2021-10-26T15:26:43.6761099 2012-01-25T14:15:44.3600000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Josie Parker 1 M Merkamm 2 N. J Manning 3 D Pompon 4 Steven Kelly 0000-0001-7991-5040 5 Diane Kelly 6
title Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
spellingShingle Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
Josie Parker
Steven Kelly
Diane Kelly
title_short Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
title_full Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
title_fullStr Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
title_full_unstemmed Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
title_sort Differential Azole Antifungal Efficacies Contrasted Using a Saccharomyces cerevisiae Strain Humanized for Sterol 14 alpha-Demethylase at the Homologous Locus
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
5ccf81e5d5beedf32ef8d7c3d7ac6c8c
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
author Josie Parker
Steven Kelly
Diane Kelly
author2 Josie Parker
M Merkamm
N. J Manning
D Pompon
Steven Kelly
Diane Kelly
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 52
container_issue 10
container_start_page 3597
publishDate 2008
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/AAC.00517-08
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 0
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description Inhibition of sterol-14&alpha;-demethylase, a cytochrome P450 (CYP51, Erg11p), is the mode of action of azole antifungal drugs, and with high frequencies of fungal infections new agents are required. New drugs that target fungal CYP51 should not inhibit human CYP51, although selective inhibitors of the human target are also of interest as anticholesterol agents. A strain of Saccharomyces cerevisiae that was humanized with respect to the amino acids encoded at the CYP51 (ERG11) yeast locus (BY4741:huCYP51) was produced. The strain was validated with respect to gene expression, protein localization, growth characteristics, and sterol content. The MIC was determined and compared to that for the wild-type parental strain (BY4741), using clotrimazole, econazole, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole. The humanized strain showed up to &gt;1,000-fold-reduced susceptibility to the orally active azole drugs, while the topical agents showed no difference. Data from growth kinetic measurements substantiated this finding but also revealed reduced effectiveness against the humanized strain for the topical drugs. Cellular sterol profiles reflected the decreased susceptibility of BY4741:huCYP51 and showed a smaller depletion of ergosterol and accumulation of 14&alpha;-methyl-ergosta-8, 24(28)-dien-3&beta;-6&alpha;-diol than the parental strain under the same treatment conditions. This strain provides a useful tool for initial specificity testing for new drugs targeting CYP51 and clearly differentiates azole antifungals in a side-by-side comparison.
published_date 2008-10-31T03:08:26Z
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