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Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity

H. J Cools, Jonathan Mullins Orcid Logo, B. A Fraaije, Josie Parker, Diane Kelly, J. A Lucas, Steven Kelly Orcid Logo

Applied and Environmental Microbiology, Volume: 77, Issue: 11, Pages: 3830 - 3837

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

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DOI (Published version): 10.1128/AEM.00027-11

Abstract

<p><span>The progressive decline in the effectiveness of some azole fungicides in controlling</span><span>Mycosphaerella graminicola</span><span>, causal agent of the damaging&nbsp;</span><span>Septoria</span><span>&nbsp;leaf blotch...

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Published in: Applied and Environmental Microbiology
ISSN: 0099-2240
Published: 2011
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URI: https://cronfa.swan.ac.uk/Record/cronfa6846
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2021-10-29T10:04:45.1118722</datestamp><bib-version>v2</bib-version><id>6846</id><entry>2012-01-25</entry><title>Impact of Recently Emerged Sterol 14&#xA0;alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity</title><swanseaauthors><author><sid>4cf2dddedbe1dacb506ec925fdbd5b40</sid><ORCID>0000-0003-0144-2962</ORCID><firstname>Jonathan</firstname><surname>Mullins</surname><name>Jonathan Mullins</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>e563ed4e1c7db8d1e131fb78a5f8d0d5</sid><firstname>Josie</firstname><surname>Parker</surname><name>Josie Parker</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><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></swanseaauthors><date>2012-01-25</date><deptcode>BMS</deptcode><abstract>&lt;p&gt;&lt;span&gt;The progressive decline in the effectiveness of some azole fungicides in controlling&lt;/span&gt;&lt;span&gt;Mycosphaerella graminicola&lt;/span&gt;&lt;span&gt;, causal agent of the damaging&amp;nbsp;&lt;/span&gt;&lt;span&gt;Septoria&lt;/span&gt;&lt;span&gt;&amp;nbsp;leaf blotch disease of wheat, has been correlated with the selection and spread in the pathogen population of specific mutations in the&amp;nbsp;&lt;/span&gt;&lt;em&gt;M. graminicola CYP51&lt;/em&gt;&lt;span&gt;&amp;nbsp;(&lt;/span&gt;&lt;em&gt;MgCYP51&lt;/em&gt;&lt;span&gt;) gene encoding the azole target sterol 14&amp;alpha;-demethylase. Recent studies have suggested that the emergence of novel MgCYP51 variants, often harboring substitution S524T, has contributed to a decrease in the efficacy of prothioconazole and epoxiconazole, the two currently most effective azole fungicides against&amp;nbsp;&lt;/span&gt;&lt;span&gt;M. graminicola&lt;/span&gt;&lt;span&gt;. In this study, we establish which amino acid alterations in novel MgCYP51 variants have the greatest impact on azole sensitivity and protein function. We introduced individual and combinations of identified alterations by site-directed mutagenesis and functionally determined their impact on azole sensitivity by expression in a&lt;/span&gt;&lt;span&gt;Saccharomyces cerevisiae&lt;/span&gt;&lt;span&gt;&amp;nbsp;mutant YUG37::&lt;/span&gt;&lt;em&gt;erg11&lt;/em&gt;&lt;span&gt;&amp;nbsp;carrying a regulatable promoter controlling native&amp;nbsp;&lt;/span&gt;&lt;em&gt;CYP51&lt;/em&gt;&lt;span&gt;&amp;nbsp;expression. We demonstrate that substitution S524T confers decreased sensitivity to all azoles when introduced alone or in combination with Y461S. In addition, S524T restores the function in&amp;nbsp;&lt;/span&gt;&lt;span&gt;S. cerevisiae&lt;/span&gt;&lt;span&gt;&amp;nbsp;of MgCYP51 variants carrying the otherwise lethal alterations Y137F and V136A. Sensitivity tests of&amp;nbsp;&lt;/span&gt;&lt;span&gt;S. cerevisiae&lt;/span&gt;&lt;span&gt;&amp;nbsp;transformants expressing recently emerged MgCYP51 variants carrying combinations of alterations D134G, V136A, Y461S, and S524T reveal a substantial impact on sensitivity to the currently most widely used azoles, including epoxiconazole and prothioconazole. Finally, we exploit a recently developed model of the MgCYP51 protein to predict that the substantial structural changes caused by these novel combinations reduce azole interactions with critical residues in the binding cavity, thereby causing resistance.&lt;/span&gt;&lt;/p&gt;</abstract><type>Journal Article</type><journal>Applied and Environmental Microbiology</journal><volume>77</volume><journalNumber>11</journalNumber><paginationStart>3830</paginationStart><paginationEnd>3837</paginationEnd><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0099-2240</issnPrint><issnElectronic/><keywords/><publishedDay>30</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2011</publishedYear><publishedDate>2011-04-30</publishedDate><doi>10.1128/AEM.00027-11</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2021-10-29T10:04:45.1118722</lastEdited><Created>2012-01-25T15:24:24.5770000</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>H. J</firstname><surname>Cools</surname><order>1</order></author><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>2</order></author><author><firstname>B. A</firstname><surname>Fraaije</surname><order>3</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>4</order></author><author><firstname>Diane</firstname><surname>Kelly</surname><order>5</order></author><author><firstname>J. A</firstname><surname>Lucas</surname><order>6</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>7</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2021-10-29T10:04:45.1118722 v2 6846 2012-01-25 Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2012-01-25 BMS <p><span>The progressive decline in the effectiveness of some azole fungicides in controlling</span><span>Mycosphaerella graminicola</span><span>, causal agent of the damaging&nbsp;</span><span>Septoria</span><span>&nbsp;leaf blotch disease of wheat, has been correlated with the selection and spread in the pathogen population of specific mutations in the&nbsp;</span><em>M. graminicola CYP51</em><span>&nbsp;(</span><em>MgCYP51</em><span>) gene encoding the azole target sterol 14&alpha;-demethylase. Recent studies have suggested that the emergence of novel MgCYP51 variants, often harboring substitution S524T, has contributed to a decrease in the efficacy of prothioconazole and epoxiconazole, the two currently most effective azole fungicides against&nbsp;</span><span>M. graminicola</span><span>. In this study, we establish which amino acid alterations in novel MgCYP51 variants have the greatest impact on azole sensitivity and protein function. We introduced individual and combinations of identified alterations by site-directed mutagenesis and functionally determined their impact on azole sensitivity by expression in a</span><span>Saccharomyces cerevisiae</span><span>&nbsp;mutant YUG37::</span><em>erg11</em><span>&nbsp;carrying a regulatable promoter controlling native&nbsp;</span><em>CYP51</em><span>&nbsp;expression. We demonstrate that substitution S524T confers decreased sensitivity to all azoles when introduced alone or in combination with Y461S. In addition, S524T restores the function in&nbsp;</span><span>S. cerevisiae</span><span>&nbsp;of MgCYP51 variants carrying the otherwise lethal alterations Y137F and V136A. Sensitivity tests of&nbsp;</span><span>S. cerevisiae</span><span>&nbsp;transformants expressing recently emerged MgCYP51 variants carrying combinations of alterations D134G, V136A, Y461S, and S524T reveal a substantial impact on sensitivity to the currently most widely used azoles, including epoxiconazole and prothioconazole. Finally, we exploit a recently developed model of the MgCYP51 protein to predict that the substantial structural changes caused by these novel combinations reduce azole interactions with critical residues in the binding cavity, thereby causing resistance.</span></p> Journal Article Applied and Environmental Microbiology 77 11 3830 3837 0099-2240 30 4 2011 2011-04-30 10.1128/AEM.00027-11 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2021-10-29T10:04:45.1118722 2012-01-25T15:24:24.5770000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine H. J Cools 1 Jonathan Mullins 0000-0003-0144-2962 2 B. A Fraaije 3 Josie Parker 4 Diane Kelly 5 J. A Lucas 6 Steven Kelly 0000-0001-7991-5040 7
title Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
spellingShingle Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
Jonathan Mullins
Josie Parker
Diane Kelly
Steven Kelly
title_short Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
title_full Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
title_fullStr Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
title_full_unstemmed Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
title_sort Impact of Recently Emerged Sterol 14 alpha-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity
author_id_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40
e563ed4e1c7db8d1e131fb78a5f8d0d5
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b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40_***_Jonathan Mullins
e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Jonathan Mullins
Josie Parker
Diane Kelly
Steven Kelly
author2 H. J Cools
Jonathan Mullins
B. A Fraaije
Josie Parker
Diane Kelly
J. A Lucas
Steven Kelly
format Journal article
container_title Applied and Environmental Microbiology
container_volume 77
container_issue 11
container_start_page 3830
publishDate 2011
institution Swansea University
issn 0099-2240
doi_str_mv 10.1128/AEM.00027-11
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 <p><span>The progressive decline in the effectiveness of some azole fungicides in controlling</span><span>Mycosphaerella graminicola</span><span>, causal agent of the damaging&nbsp;</span><span>Septoria</span><span>&nbsp;leaf blotch disease of wheat, has been correlated with the selection and spread in the pathogen population of specific mutations in the&nbsp;</span><em>M. graminicola CYP51</em><span>&nbsp;(</span><em>MgCYP51</em><span>) gene encoding the azole target sterol 14&alpha;-demethylase. Recent studies have suggested that the emergence of novel MgCYP51 variants, often harboring substitution S524T, has contributed to a decrease in the efficacy of prothioconazole and epoxiconazole, the two currently most effective azole fungicides against&nbsp;</span><span>M. graminicola</span><span>. In this study, we establish which amino acid alterations in novel MgCYP51 variants have the greatest impact on azole sensitivity and protein function. We introduced individual and combinations of identified alterations by site-directed mutagenesis and functionally determined their impact on azole sensitivity by expression in a</span><span>Saccharomyces cerevisiae</span><span>&nbsp;mutant YUG37::</span><em>erg11</em><span>&nbsp;carrying a regulatable promoter controlling native&nbsp;</span><em>CYP51</em><span>&nbsp;expression. We demonstrate that substitution S524T confers decreased sensitivity to all azoles when introduced alone or in combination with Y461S. In addition, S524T restores the function in&nbsp;</span><span>S. cerevisiae</span><span>&nbsp;of MgCYP51 variants carrying the otherwise lethal alterations Y137F and V136A. Sensitivity tests of&nbsp;</span><span>S. cerevisiae</span><span>&nbsp;transformants expressing recently emerged MgCYP51 variants carrying combinations of alterations D134G, V136A, Y461S, and S524T reveal a substantial impact on sensitivity to the currently most widely used azoles, including epoxiconazole and prothioconazole. Finally, we exploit a recently developed model of the MgCYP51 protein to predict that the substantial structural changes caused by these novel combinations reduce azole interactions with critical residues in the binding cavity, thereby causing resistance.</span></p>
published_date 2011-04-30T03:08:26Z
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score 11.016235

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