{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:59:03Z","timestamp":1791273543178,"version":"4.1.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Antifungal resistance of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida<\/jats:named-content>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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida<\/jats:named-content>species (<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida albicans<\/jats:named-content>JEY355 and<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Candida tropicalis<\/jats:named-content>JEY162) with decreased susceptibility to azoles and polyenes. For JEY355, the fluconazole (FLC) MIC was 8 \u03bcg\/ml. Azole resistance in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>JEY355 was mainly caused by overexpression of a multidrug efflux pump of the major facilitator superfamily, Mdr1. The regulator of Mdr1,<jats:italic>MRR1<\/jats:italic>, contained a yet-unknown gain-of-function mutation (V877F) causing<jats:italic>MDR1<\/jats:italic>overexpression. The<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. tropicalis<\/jats:named-content>JEY162 isolate demonstrated cross-resistance between FLC (MIC &gt; 128 \u03bcg\/ml), voriconazole (MIC &gt; 16 \u03bcg\/ml), and amphotericin B (MIC &gt; 32 \u03bcg\/ml). Sterol analysis using gas chromatography-mass spectrometry revealed that ergosterol was undetectable in JEY162 and that it accumulated 14\u03b1-methyl fecosterol, thus indicating a perturbation in the function of at least two main ergosterol biosynthesis proteins (Erg11 and Erg3). Sequence analyses of<jats:italic>C. tropicalis ERG11<\/jats:italic>(<jats:italic>CtERG11<\/jats:italic>) and<jats:italic>CtERG3<\/jats:italic>from JEY162 revealed a deletion of 132 nucleotides and a single amino acid substitution (S258F), respectively. These two alleles were demonstrated to be nonfunctional and thus are consistent with previous studies showing that<jats:italic>ERG11<\/jats:italic>mutants can only survive in combination with other<jats:italic>ERG3<\/jats:italic>mutations.<jats:italic>CtERG3<\/jats:italic>and<jats:italic>CtERG11<\/jats:italic>wild-type alleles were replaced by the defective genes in a wild-type<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. tropicalis<\/jats:named-content>strain, resulting in a drug resistance phenotype identical to that of JEY162. This genetic evidence demonstrated that<jats:italic>CtERG3<\/jats:italic>and<jats:italic>CtERG11<\/jats:italic>mutations participated in drug resistance. During reconstitution of the drug resistance in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. tropicalis<\/jats:named-content>, a strain was obtained harboring only defective<jats:italic>Cterg11<\/jats:italic>allele and containing as a major sterol the toxic metabolite 14\u03b1-methyl-ergosta-8,24(28)-dien-3\u03b1,6\u03b2-diol, suggesting that<jats:italic>ERG3<\/jats:italic>was still functional. This strain therefore challenged the current belief that<jats:italic>ERG11<\/jats:italic>mutations cannot be viable unless accompanied by compensatory mutations. In conclusion, this study, in addition to identifying a novel<jats:italic>MRR1<\/jats:italic>mutation in<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. albicans<\/jats:named-content>, constitutes the first report on a clinical<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">C. tropicalis<\/jats:named-content>with defective activity of sterol 14\u03b1-demethylase and sterol \u0394<jats:sup>5,6<\/jats:sup>-desaturase leading to azole-polyene cross-resistance.<\/jats:p>","DOI":"10.1128\/aac.00555-13","type":"journal-article","created":{"date-parts":[[2013,4,30]],"date-time":"2013-04-30T03:01:41Z","timestamp":1367290901000},"page":"3182-3193","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":114,"title":["Molecular Mechanisms of Drug Resistance in Clinical Candida Species 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Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Coste","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Ischer","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Kelly","sequence":"additional","affiliation":[{"name":"Institute of Life Science and College of Medicine, Swansea University, Swansea, Wales, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Manai","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Molecular Biology, Faculty of Sciences of Tunis, Campus Universitaire El-Manar, Tunis, 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