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Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals

J Eddouzi, Josie Parker, L. A Vale-Silva, A Coste, F Ischer, Steven Kelly Orcid Logo, M Manai, D Sanglard

Antimicrobial Agents and Chemotherapy, Volume: 57, Issue: 7, Pages: 3182 - 3193

Swansea University Authors: Josie Parker, Steven Kelly Orcid Logo

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DOI (Published version): 10.1128/AAC.00555-13

Abstract

Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with...

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Published in: Antimicrobial Agents and Chemotherapy
ISSN: 0066-4804 1098-6596
Published: 2013
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URI: https://cronfa.swan.ac.uk/Record/cronfa15187
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2021-10-26T16:58:03.4614045</datestamp><bib-version>v2</bib-version><id>15187</id><entry>2013-07-11</entry><title>Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals</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>2013-07-11</date><deptcode>FGMHL</deptcode><abstract>Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with decreased susceptibility to azoles and polyenes. JEY355 exhibited fluconazole MIC of 8 &#x3BC;g/ml. Azole-resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet unknown gain-of-function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate showed cross-resistance between FLC (MIC &gt;128 &#x3BC;g/ml), voriconazole (MIC &gt;16 &#x3BC;g/ml) and amphotericin B (MIC &gt;32 &#x3BC;g/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14&#x3B1;-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of CtERG11 and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated as non-functional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain resulting in drug resistance phenotype identical to JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as major sterol the toxic metabolite 14&#x3B1;-methyl-ergosta-8,24 (28)-dien-3&#x3B1;, 6&#x3B2;-diol, thus suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, besides identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14&#x3B1;-demethylase and sterol &#x394;5,6-desaturase leading to azole-polyene cross-resistance.</abstract><type>Journal Article</type><journal>Antimicrobial Agents and Chemotherapy</journal><volume>57</volume><journalNumber>7</journalNumber><paginationStart>3182</paginationStart><paginationEnd>3193</paginationEnd><publisher/><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0066-4804</issnPrint><issnElectronic>1098-6596</issnElectronic><keywords/><publishedDay>31</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2013</publishedYear><publishedDate>2013-12-31</publishedDate><doi>10.1128/AAC.00555-13</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>2021-10-26T16:58:03.4614045</lastEdited><Created>2013-07-11T11:16:55.0000105</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>J</firstname><surname>Eddouzi</surname><order>1</order></author><author><firstname>Josie</firstname><surname>Parker</surname><order>2</order></author><author><firstname>L. A</firstname><surname>Vale-Silva</surname><order>3</order></author><author><firstname>A</firstname><surname>Coste</surname><order>4</order></author><author><firstname>F</firstname><surname>Ischer</surname><order>5</order></author><author><firstname>Steven</firstname><surname>Kelly</surname><orcid>0000-0001-7991-5040</orcid><order>6</order></author><author><firstname>M</firstname><surname>Manai</surname><order>7</order></author><author><firstname>D</firstname><surname>Sanglard</surname><order>8</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2021-10-26T16:58:03.4614045 v2 15187 2013-07-11 Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false b17cebaf09b4d737b9378a3581e3de93 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2013-07-11 FGMHL Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with decreased susceptibility to azoles and polyenes. JEY355 exhibited fluconazole MIC of 8 μg/ml. Azole-resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet unknown gain-of-function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate showed cross-resistance between FLC (MIC >128 μg/ml), voriconazole (MIC >16 μg/ml) and amphotericin B (MIC >32 μg/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14α-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of CtERG11 and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated as non-functional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain resulting in drug resistance phenotype identical to JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as major sterol the toxic metabolite 14α-methyl-ergosta-8,24 (28)-dien-3α, 6β-diol, thus suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, besides identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14α-demethylase and sterol Δ5,6-desaturase leading to azole-polyene cross-resistance. Journal Article Antimicrobial Agents and Chemotherapy 57 7 3182 3193 0066-4804 1098-6596 31 12 2013 2013-12-31 10.1128/AAC.00555-13 COLLEGE NANME Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL Swansea University 2021-10-26T16:58:03.4614045 2013-07-11T11:16:55.0000105 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine J Eddouzi 1 Josie Parker 2 L. A Vale-Silva 3 A Coste 4 F Ischer 5 Steven Kelly 0000-0001-7991-5040 6 M Manai 7 D Sanglard 8
title Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
spellingShingle Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
Josie Parker
Steven Kelly
title_short Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
title_full Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
title_fullStr Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
title_full_unstemmed Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
title_sort Molecular Mechanisms of Drug Resistance in Clinical Candida Species Isolated from Tunisian Hospitals
author_id_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5
b17cebaf09b4d737b9378a3581e3de93
author_id_fullname_str_mv e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker
b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly
author Josie Parker
Steven Kelly
author2 J Eddouzi
Josie Parker
L. A Vale-Silva
A Coste
F Ischer
Steven Kelly
M Manai
D Sanglard
format Journal article
container_title Antimicrobial Agents and Chemotherapy
container_volume 57
container_issue 7
container_start_page 3182
publishDate 2013
institution Swansea University
issn 0066-4804
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doi_str_mv 10.1128/AAC.00555-13
college_str Faculty of Medicine, Health and Life Sciences
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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 Antifungal resistance of Candida species is a clinical problem in the management of diseases caused by these pathogens. In this study we identified from a collection of 423 clinical samples taken from Tunisian hospitals two clinical Candida species (C. albicans JEY355 and C. tropicalis JEY162) with decreased susceptibility to azoles and polyenes. JEY355 exhibited fluconazole MIC of 8 μg/ml. Azole-resistance in C. albicans JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1, MRR1, contained a yet unknown gain-of-function mutation (V877F) causing MDR1 overexpression. The C. tropicalis JEY162 isolate showed cross-resistance between FLC (MIC >128 μg/ml), voriconazole (MIC >16 μg/ml) and amphotericin B (MIC >32 μg/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14α-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of CtERG11 and CtERG3 from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated as non-functional and thus are consistent with previous studies showing that ERG11 mutants can only survive in combination with other ERG3 mutations. CtERG3 and CtERG11 wild-type alleles were replaced by the defective genes in a wild-type C. tropicalis strain resulting in drug resistance phenotype identical to JEY162. This genetic evidence demonstrated that CtERG3 and CtERG11 mutations participated in drug resistance. During reconstitution of the drug resistance in C. tropicalis, a strain was obtained harboring only defective Cterg11 allele and containing as major sterol the toxic metabolite 14α-methyl-ergosta-8,24 (28)-dien-3α, 6β-diol, thus suggesting that ERG3 was still functional. This strain therefore challenged the current belief that ERG11 mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, besides identifying a novel MRR1 mutation in C. albicans, constitutes the first report on a clinical C. tropicalis with defective activity of sterol 14α-demethylase and sterol Δ5,6-desaturase leading to azole-polyene cross-resistance.
published_date 2013-12-31T03:17:18Z
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score 11.017084

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