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ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait

Suhail Ahmad, Leena Joseph, Josie Parker, Mohammad Asadzadeh, Steven Kelly Orcid Logo, Jacques F. Meis, Ziauddin Khan

Antimicrobial Agents and Chemotherapy, Volume: 63, Issue: 2, Start page: e01900-18

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/AAC.01900-18

Abstract

Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2018
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URI: https://cronfa.swan.ac.uk/Record/cronfa45903
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spelling 2020-07-17T13:16:36.0403611 v2 45903 2018-11-12 ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2018-11-12 FGMHL Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1646 C. glabrata isolates were tested by Etest and results for 12 selected isolates were confirmed by reference broth microdilution. PCR-sequencing of three (ERG2, ERG6 and ERG11) genes was performed for all RS-AMB and 5 selected wild-type C. glabrata isolates by using gene-specific primers. Total cell sterol content was analyzed by gas chromatography-mass spectrometry. Phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6 or ERG11 and total sterol content was similar to reference strains. A nonsynonymous (AGA48AAA, R48K) ERG6 mutation was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286/Tyr192/Leu341 and 2 isolates contained nonsynonymous (V126F or C198F) mutation in ERG6 and their sterol content were consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous (G119S or G122S) ERG2 mutation and their sterol content were consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H+L381M mutations while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6/ERG2/ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates. Journal Article Antimicrobial Agents and Chemotherapy 63 2 e01900-18 0066-4804 1098-6596 19 11 2018 2018-11-19 10.1128/AAC.01900-18 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2020-07-17T13:16:36.0403611 2018-11-12T14:16:55.2891878 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Suhail Ahmad 1 Leena Joseph 2 Josie Parker 3 Mohammad Asadzadeh 4 Steven Kelly 0000-0001-7991-5040 5 Jacques F. Meis 6 Ziauddin Khan 7 0045903-12112018141921.pdf 45903.pdf 2018-11-12T14:19:21.6070000 Output 255085 application/pdf Accepted Manuscript true 2019-05-19T00:00:00.0000000 true eng
title ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
spellingShingle ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
Josie Parker
Steven Kelly
title_short ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
title_full ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
title_fullStr ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
title_full_unstemmed ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
title_sort ERG6 and ERG2 Are Major Targets Conferring Reduced Susceptibility to Amphotericin B in Clinical Candida glabrata Isolates in Kuwait
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Josie Parker
Steven Kelly
author2 Suhail Ahmad
Leena Joseph
Josie Parker
Mohammad Asadzadeh
Steven Kelly
Jacques F. Meis
Ziauddin Khan
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 63
container_issue 2
container_start_page e01900-18
publishDate 2018
institution Swansea University
issn 0066-4804
1098-6596
doi_str_mv 10.1128/AAC.01900-18
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
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description Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1646 C. glabrata isolates were tested by Etest and results for 12 selected isolates were confirmed by reference broth microdilution. PCR-sequencing of three (ERG2, ERG6 and ERG11) genes was performed for all RS-AMB and 5 selected wild-type C. glabrata isolates by using gene-specific primers. Total cell sterol content was analyzed by gas chromatography-mass spectrometry. Phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6 or ERG11 and total sterol content was similar to reference strains. A nonsynonymous (AGA48AAA, R48K) ERG6 mutation was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286/Tyr192/Leu341 and 2 isolates contained nonsynonymous (V126F or C198F) mutation in ERG6 and their sterol content were consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous (G119S or G122S) ERG2 mutation and their sterol content were consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H+L381M mutations while 7 isolates contained only synonymous mutations in ERG11. All isolates with ERG6/ERG2/ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates.
published_date 2018-11-19T03:57:34Z
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score 11.016593

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