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Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr
Microbiology Spectrum, Volume: 11, Issue: 4
Swansea University Author: Steven Kelly
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DOI (Published version): 10.1128/spectrum.01474-23
Abstract
The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 pa...
Published in: | Microbiology Spectrum |
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ISSN: | 2165-0497 |
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American Society for Microbiology
2023
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<?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>64121</id><entry>2023-08-23</entry><title>Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr</title><swanseaauthors><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>2023-08-23</date><deptcode>BMS</deptcode><abstract>The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 patients in Kuwait and identified by phenotypic and molecular methods were analyzed. An Etest was initially used to identify isolates with rs-AMB. Specific mutations in ERG2 and ERG6 involved in ergosterol biosynthesis were detected by PCR sequencing. Twelve selected isolates were also tested by the SensiTitre Yeast One (SYO), and total cell sterols were evaluated by gas chromatography-mass spectrometry and ERG3 and ERG11 sequencing. Eight isolates from 8 patients showed rs-AMB by Etest, including 2 isolates with additional resistance to fluconazole or to all three antifungals. SYO correctly identified 8 of 8 rs-AMB isolates. A nonsynonymous mutation in ERG2 was detected in 6 of 8 rs-AMB isolates but also in 3 of 73 isolates with a wild-type AMB pattern. One rs-AMB isolate contained a deletion (frameshift) mutation in ERG2. One or more nonsynonymous mutations was detected in ERG6 in 11 of 81 isolates with the rs-AMB or wild-type AMB pattern. Among 12 selected isolates, 2 and 2 isolates contained a nonsynonymous mutation(s) in ERG3 and ERG11, respectively. Ergosterol was undetectable in 7 of 8 rs-AMB isolates, and the total cell sterol profiles were consistent with loss of ERG2 function in 6 rs-AMB isolates and loss of ERG3 activity in another rs-AMB isolate. Our data showed that ERG2 is a major target conferring rs-AMB in clinical C. kefyr isolates.</abstract><type>Journal Article</type><journal>Microbiology Spectrum</journal><volume>11</volume><journalNumber>4</journalNumber><paginationStart/><paginationEnd/><publisher>American Society for Microbiology</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2165-0497</issnElectronic><keywords>Candida kefyr, ERG2, nonsynonymous mutations, reduced susceptibility, amphotericin B</keywords><publishedDay>17</publishedDay><publishedMonth>8</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-08-17</publishedDate><doi>10.1128/spectrum.01474-23</doi><url>http://dx.doi.org/10.1128/spectrum.01474-23</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This study was supported and funded by Kuwait University Research Sector grant MI
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v2 64121 2023-08-23 Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2023-08-23 BMS The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 patients in Kuwait and identified by phenotypic and molecular methods were analyzed. An Etest was initially used to identify isolates with rs-AMB. Specific mutations in ERG2 and ERG6 involved in ergosterol biosynthesis were detected by PCR sequencing. Twelve selected isolates were also tested by the SensiTitre Yeast One (SYO), and total cell sterols were evaluated by gas chromatography-mass spectrometry and ERG3 and ERG11 sequencing. Eight isolates from 8 patients showed rs-AMB by Etest, including 2 isolates with additional resistance to fluconazole or to all three antifungals. SYO correctly identified 8 of 8 rs-AMB isolates. A nonsynonymous mutation in ERG2 was detected in 6 of 8 rs-AMB isolates but also in 3 of 73 isolates with a wild-type AMB pattern. One rs-AMB isolate contained a deletion (frameshift) mutation in ERG2. One or more nonsynonymous mutations was detected in ERG6 in 11 of 81 isolates with the rs-AMB or wild-type AMB pattern. Among 12 selected isolates, 2 and 2 isolates contained a nonsynonymous mutation(s) in ERG3 and ERG11, respectively. Ergosterol was undetectable in 7 of 8 rs-AMB isolates, and the total cell sterol profiles were consistent with loss of ERG2 function in 6 rs-AMB isolates and loss of ERG3 activity in another rs-AMB isolate. Our data showed that ERG2 is a major target conferring rs-AMB in clinical C. kefyr isolates. Journal Article Microbiology Spectrum 11 4 American Society for Microbiology 2165-0497 Candida kefyr, ERG2, nonsynonymous mutations, reduced susceptibility, amphotericin B 17 8 2023 2023-08-17 10.1128/spectrum.01474-23 http://dx.doi.org/10.1128/spectrum.01474-23 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee This study was supported and funded by Kuwait University Research Sector grant MI 02/20. 2023-10-02T11:23:46.7363665 2023-08-23T15:17:44.3119864 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Mohammad Asadzadeh 1 Wadha Alfouzan 2 Josie E. Parker 3 Jacques F. Meis 0000-0003-3253-6080 4 Steven Kelly 0000-0001-7991-5040 5 Leena Joseph 6 Suhail Ahmad 0000-0003-3492-4781 7 64121__28672__4d21c38677914408846df6e80e16e3cd.pdf 64121.VOR.pdf 2023-10-02T11:22:02.3727239 Output 318752 application/pdf Version of Record true Upon publication, the work becomes available to the public under a Creative Commons CC BY 4.0 license. Users have the right to read, download, copy, distribute, print, search, or link to the full texts of open access articles with attribution. true eng https://creativecommons.org/licenses/by/4.0/ |
title |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
spellingShingle |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr Steven Kelly |
title_short |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
title_full |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
title_fullStr |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
title_full_unstemmed |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
title_sort |
Molecular Characterization and Sterol Profiles Identify Nonsynonymous Mutations in ERG2 as a Major Mechanism Conferring Reduced Susceptibility to Amphotericin B in Candida kefyr |
author_id_str_mv |
b17cebaf09b4d737b9378a3581e3de93 |
author_id_fullname_str_mv |
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly |
author |
Steven Kelly |
author2 |
Mohammad Asadzadeh Wadha Alfouzan Josie E. Parker Jacques F. Meis Steven Kelly Leena Joseph Suhail Ahmad |
format |
Journal article |
container_title |
Microbiology Spectrum |
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11 |
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4 |
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2023 |
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Swansea University |
issn |
2165-0497 |
doi_str_mv |
10.1128/spectrum.01474-23 |
publisher |
American Society for Microbiology |
college_str |
Faculty of Medicine, Health and Life Sciences |
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|
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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Faculty of Medicine, Health and Life Sciences |
department_str |
Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science |
url |
http://dx.doi.org/10.1128/spectrum.01474-23 |
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description |
The molecular basis of reduced susceptibility to amphotericin B (rs-AMB) among any yeasts is poorly defined. Genetic alterations in genes involved in ergosterol biosynthesis and total cell sterols were investigated among clinical Candida kefyr isolates. C. kefyr isolates (n = 81) obtained from 74 patients in Kuwait and identified by phenotypic and molecular methods were analyzed. An Etest was initially used to identify isolates with rs-AMB. Specific mutations in ERG2 and ERG6 involved in ergosterol biosynthesis were detected by PCR sequencing. Twelve selected isolates were also tested by the SensiTitre Yeast One (SYO), and total cell sterols were evaluated by gas chromatography-mass spectrometry and ERG3 and ERG11 sequencing. Eight isolates from 8 patients showed rs-AMB by Etest, including 2 isolates with additional resistance to fluconazole or to all three antifungals. SYO correctly identified 8 of 8 rs-AMB isolates. A nonsynonymous mutation in ERG2 was detected in 6 of 8 rs-AMB isolates but also in 3 of 73 isolates with a wild-type AMB pattern. One rs-AMB isolate contained a deletion (frameshift) mutation in ERG2. One or more nonsynonymous mutations was detected in ERG6 in 11 of 81 isolates with the rs-AMB or wild-type AMB pattern. Among 12 selected isolates, 2 and 2 isolates contained a nonsynonymous mutation(s) in ERG3 and ERG11, respectively. Ergosterol was undetectable in 7 of 8 rs-AMB isolates, and the total cell sterol profiles were consistent with loss of ERG2 function in 6 rs-AMB isolates and loss of ERG3 activity in another rs-AMB isolate. Our data showed that ERG2 is a major target conferring rs-AMB in clinical C. kefyr isolates. |
published_date |
2023-08-17T11:23:49Z |
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11.016235 |