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In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris

Jeffrey M. Rybak, Katherine S. Barker, José F. Muñoz, Josie Parker, Suhail Ahmad, Eiman Mokaddas, Aneesa Abdullah, Rehab S. Elhagracy, Steven Kelly Orcid Logo, Christina A. Cuomo, P. David Rogers

Clinical Microbiology and Infection, Volume: 28, Issue: 6, Pages: 838 - 843

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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DOI (Published version): 10.1016/j.cmi.2021.11.024

Abstract

ObjectiveCandida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here...

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Published in: Clinical Microbiology and Infection
ISSN: 1198-743X
Published: Elsevier BV 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa59077
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2022-10-07T11:28:56.8320950</datestamp><bib-version>v2</bib-version><id>59077</id><entry>2022-01-05</entry><title>In&#xA0;vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris</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>2022-01-05</date><deptcode>FGMHL</deptcode><abstract>ObjectiveCandida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance.MethodsWhole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling.ResultsA novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a &gt;32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation.ConclusionsTogether these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat.</abstract><type>Journal Article</type><journal>Clinical Microbiology and Infection</journal><volume>28</volume><journalNumber>6</journalNumber><paginationStart>838</paginationStart><paginationEnd>843</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1198-743X</issnPrint><issnElectronic/><keywords>amphotericin B; Candida auris; ERG6; In vivo evolution; Resistance</keywords><publishedDay>1</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-06-01</publishedDate><doi>10.1016/j.cmi.2021.11.024</doi><url>http://dx.doi.org/10.1016/j.cmi.2021.11.024</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/><funders>National Institutes of Health (USA).</funders><projectreference/><lastEdited>2022-10-07T11:28:56.8320950</lastEdited><Created>2022-01-05T09:16:04.8935084</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>Jeffrey M.</firstname><surname>Rybak</surname><order>1</order></author><author><firstname>Katherine S.</firstname><surname>Barker</surname><order>2</order></author><author><firstname>Jos&#xE9; F.</firstname><surname>Mu&#xF1;oz</surname><order>3</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>4</order></author><author><firstname>Suhail</firstname><surname>Ahmad</surname><order>5</order></author><author><firstname>Eiman</firstname><surname>Mokaddas</surname><order>6</order></author><author><firstname>Aneesa</firstname><surname>Abdullah</surname><order>7</order></author><author><firstname>Rehab S.</firstname><surname>Elhagracy</surname><order>8</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>9</order></author><author><firstname>Christina A.</firstname><surname>Cuomo</surname><order>10</order></author><author><firstname>P. David</firstname><surname>Rogers</surname><order>11</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2022-10-07T11:28:56.8320950 v2 59077 2022-01-05 In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2022-01-05 FGMHL ObjectiveCandida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance.MethodsWhole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling.ResultsA novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a >32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation.ConclusionsTogether these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat. Journal Article Clinical Microbiology and Infection 28 6 838 843 Elsevier BV 1198-743X amphotericin B; Candida auris; ERG6; In vivo evolution; Resistance 1 6 2022 2022-06-01 10.1016/j.cmi.2021.11.024 http://dx.doi.org/10.1016/j.cmi.2021.11.024 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University National Institutes of Health (USA). 2022-10-07T11:28:56.8320950 2022-01-05T09:16:04.8935084 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Jeffrey M. Rybak 1 Katherine S. Barker 2 José F. Muñoz 3 Josie Parker 4 Suhail Ahmad 5 Eiman Mokaddas 6 Aneesa Abdullah 7 Rehab S. Elhagracy 8 Steven Kelly 0000-0001-7991-5040 9 Christina A. Cuomo 10 P. David Rogers 11
title In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
spellingShingle In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
Josie Parker
Steven Kelly
title_short In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
title_full In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
title_fullStr In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
title_full_unstemmed In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
title_sort In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Josie Parker
Steven Kelly
author2 Jeffrey M. Rybak
Katherine S. Barker
José F. Muñoz
Josie Parker
Suhail Ahmad
Eiman Mokaddas
Aneesa Abdullah
Rehab S. Elhagracy
Steven Kelly
Christina A. Cuomo
P. David Rogers
format Journal article
container_title Clinical Microbiology and Infection
container_volume 28
container_issue 6
container_start_page 838
publishDate 2022
institution Swansea University
issn 1198-743X
doi_str_mv 10.1016/j.cmi.2021.11.024
publisher Elsevier BV
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
url http://dx.doi.org/10.1016/j.cmi.2021.11.024
document_store_str 0
active_str 0
description ObjectiveCandida auris has emerged as a health-care-associated and multidrug-resistant fungal pathogen of great clinical concern. As many as 50% of C. auris clinical isolates are reported to be resistant to amphotericin B, but no mechanisms contributing to this resistance have been identified. Here we describe a clinical case in which high-level amphotericin B resistance was acquired in vivo during therapy and undertake molecular and genetic studies to identify and characterize the genetic determinant of resistance.MethodsWhole-genome sequencing was performed on four C. auris isolates obtained from a single patient case. Cas9-mediated genetic manipulations were then used to generate mutant strains harbouring mutations of interest, and these strains were subsequently subjected to amphotericin B susceptibility testing and comprehensive sterol profiling.ResultsA novel mutation in the C. auris sterol-methyltransferase gene ERG6 was found to be associated with amphotericin B resistance, and this mutation alone conferred a >32-fold increase in amphotericin B resistance. Comprehensive sterol profiling revealed an abrogation of ergosterol biosynthesis and a corresponding accumulation of cholesta-type sterols in isolates and strains harbouring the clinically derived ERG6 mutation.ConclusionsTogether these findings definitively demonstrate mutations in C. auris ERG6 as the first identified mechanism of clinical amphotericin B resistance in C. auris and represent a significant step forward in the understanding of antifungal resistance in this emerging public health threat.
published_date 2022-06-01T04:16:06Z
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score 10.97096

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