Journal article 1280 views
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence
L. A. Vale-Silva,
A. T. Coste,
F. Ischer,
Josie Parker,
Steven Kelly 
,
E. Pinto,
D. Sanglard
,
E. Pinto,
D. Sanglard
Antimicrobial Agents and Chemotherapy, Volume: 56, Issue: 4, Pages: 1960 - 1968
Swansea University Authors:
Josie Parker, Steven Kelly
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DOI (Published version): 10.1128/aac.05720-11
Abstract
<p><span>The inactivation of ERG3, a gene encoding sterol Δ(5,6)-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of fila...
| Published in: | Antimicrobial Agents and Chemotherapy |
|---|---|
| ISSN: | 0066-4804 1098-6596 |
| Published: |
American Society for Microbiology
2012
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa6836 |
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<?xml version="1.0"?><rfc1807><datestamp>2021-10-29T09:41:54.8638288</datestamp><bib-version>v2</bib-version><id>6836</id><entry>2012-01-25</entry><title>Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence</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></swanseaauthors><date>2012-01-25</date><deptcode>FGMHL</deptcode><abstract><p><span>The inactivation of ERG3, a gene encoding sterol &Delta;(5,6)-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a C. albicans clinical isolate (VSY2) with high level resistance to azole drugs in vitro and absence of ergosterol but normal filamentation. Sequencing of ERG3 in VSY2 revealed a double base deletion leading to a premature stop codon and thus a non-functional enzyme. The reversion of the double base deletion in the mutant allele (erg3-1) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that ERG3 inactivation was the mechanism of azole resistance. Additionally, the replacement of both ERG3 alleles by erg3-1 in the wild type strain SC5314 led to the absence of ergosterol and fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical ERG3 mutant VSY2 produced kidney fungal burdens and mice survival comparable to the wild type control. Interestingly, while VSY2 was resistant to fluconazole both in vitro and in vivo, the ERG3-derived mutant from SC5314 was only resistant in vitro and was less virulent than the wild type. This suggests that VSY2 compensated the in vivo fitness defect of ERG3 inactivation by still unknown mechanism(s). Taken together, our results provide evidence that, contrary to previous studies, inactivation of ERG3 does not necessarily affect filamentation and virulence.</span></p></abstract><type>Journal Article</type><journal>Antimicrobial Agents and Chemotherapy</journal><volume>56</volume><journalNumber>4</journalNumber><paginationStart>1960</paginationStart><paginationEnd>1968</paginationEnd><publisher>American Society for Microbiology</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0066-4804</issnPrint><issnElectronic>1098-6596</issnElectronic><keywords/><publishedDay>1</publishedDay><publishedMonth>4</publishedMonth><publishedYear>2012</publishedYear><publishedDate>2012-04-01</publishedDate><doi>10.1128/aac.05720-11</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>2021-10-29T09:41:54.8638288</lastEdited><Created>2012-01-25T14:22:12.8670000</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>L. A.</firstname><surname>Vale-Silva</surname><order>1</order></author><author><firstname>A. T.</firstname><surname>Coste</surname><order>2</order></author><author><firstname>F.</firstname><surname>Ischer</surname><order>3</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>4</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>5</order></author><author><firstname>E.</firstname><surname>Pinto</surname><order>6</order></author><author><firstname>D.</firstname><surname>Sanglard</surname><order>7</order></author></authors><documents/><OutputDurs/></rfc1807> |
| spelling |
2021-10-29T09:41:54.8638288 v2 6836 2012-01-25 Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2012-01-25 FGMHL <p><span>The inactivation of ERG3, a gene encoding sterol Δ(5,6)-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a C. albicans clinical isolate (VSY2) with high level resistance to azole drugs in vitro and absence of ergosterol but normal filamentation. Sequencing of ERG3 in VSY2 revealed a double base deletion leading to a premature stop codon and thus a non-functional enzyme. The reversion of the double base deletion in the mutant allele (erg3-1) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that ERG3 inactivation was the mechanism of azole resistance. Additionally, the replacement of both ERG3 alleles by erg3-1 in the wild type strain SC5314 led to the absence of ergosterol and fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical ERG3 mutant VSY2 produced kidney fungal burdens and mice survival comparable to the wild type control. Interestingly, while VSY2 was resistant to fluconazole both in vitro and in vivo, the ERG3-derived mutant from SC5314 was only resistant in vitro and was less virulent than the wild type. This suggests that VSY2 compensated the in vivo fitness defect of ERG3 inactivation by still unknown mechanism(s). Taken together, our results provide evidence that, contrary to previous studies, inactivation of ERG3 does not necessarily affect filamentation and virulence.</span></p> Journal Article Antimicrobial Agents and Chemotherapy 56 4 1960 1968 American Society for Microbiology 0066-4804 1098-6596 1 4 2012 2012-04-01 10.1128/aac.05720-11 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2021-10-29T09:41:54.8638288 2012-01-25T14:22:12.8670000 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine L. A. Vale-Silva 1 A. T. Coste 2 F. Ischer 3 Josie Parker 4 Steven Kelly 0000-0001-7991-5040 5 E. Pinto 6 D. Sanglard 7 |
| title |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| spellingShingle |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence Josie Parker Steven Kelly |
| title_short |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| title_full |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| title_fullStr |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| title_full_unstemmed |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| title_sort |
Azole Resistance by Loss of Function of the Sterol Δ5,6-Desaturase Gene (ERG3) in Candida albicans Does Not Necessarily Decrease Virulence |
| author_id_str_mv |
e563ed4e1c7db8d1e131fb78a5f8d0d5 b17cebaf09b4d737b9378a3581e3de93 |
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e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly |
| author |
Josie Parker Steven Kelly |
| author2 |
L. A. Vale-Silva A. T. Coste F. Ischer Josie Parker Steven Kelly E. Pinto D. Sanglard |
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Journal article |
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Antimicrobial Agents and Chemotherapy |
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56 |
| container_issue |
4 |
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1960 |
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2012 |
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Swansea University |
| issn |
0066-4804 1098-6596 |
| doi_str_mv |
10.1128/aac.05720-11 |
| publisher |
American Society for Microbiology |
| college_str |
Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine |
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| description |
<p><span>The inactivation of ERG3, a gene encoding sterol Δ(5,6)-desaturase (essential for ergosterol biosynthesis), is a known mechanism of in vitro resistance to azole antifungal drugs in the human pathogen Candida albicans. ERG3 inactivation typically results in loss of filamentation and attenuated virulence in animal models of disseminated candidiasis. In this work, we identified a C. albicans clinical isolate (VSY2) with high level resistance to azole drugs in vitro and absence of ergosterol but normal filamentation. Sequencing of ERG3 in VSY2 revealed a double base deletion leading to a premature stop codon and thus a non-functional enzyme. The reversion of the double base deletion in the mutant allele (erg3-1) restored ergosterol biosynthesis and full fluconazole susceptibility in VSY2, confirming that ERG3 inactivation was the mechanism of azole resistance. Additionally, the replacement of both ERG3 alleles by erg3-1 in the wild type strain SC5314 led to the absence of ergosterol and fluconazole resistance without affecting filamentation. In a mouse model of disseminated candidiasis, the clinical ERG3 mutant VSY2 produced kidney fungal burdens and mice survival comparable to the wild type control. Interestingly, while VSY2 was resistant to fluconazole both in vitro and in vivo, the ERG3-derived mutant from SC5314 was only resistant in vitro and was less virulent than the wild type. This suggests that VSY2 compensated the in vivo fitness defect of ERG3 inactivation by still unknown mechanism(s). Taken together, our results provide evidence that, contrary to previous studies, inactivation of ERG3 does not necessarily affect filamentation and virulence.</span></p> |
| published_date |
2012-04-01T03:08:26Z |
| _version_ |
1763749822533206016 |
| score |
10.998184 |