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Resistance to azoles can occur in\n            <jats:named-content content-type=\"genus-species\">Candida albicans<\/jats:named-content>\n            principally by overexpression of multidrug transporter gene\n            <jats:italic>CDR1<\/jats:italic>\n            ,\n            <jats:italic>CDR2<\/jats:italic>\n            , or\n            <jats:italic>MDR1<\/jats:italic>\n            or by overexpression of\n            <jats:italic>ERG11<\/jats:italic>\n            , which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs)\n            <jats:italic>TAC1<\/jats:italic>\n            (involved in the control of\n            <jats:italic>CDR1<\/jats:italic>\n            and\n            <jats:italic>CDR2<\/jats:italic>\n            ),\n            <jats:italic>MRR1<\/jats:italic>\n            (involved in the control of\n            <jats:italic>MDR1<\/jats:italic>\n            ), and\n            <jats:italic>UPC2<\/jats:italic>\n            (involved in the control of\n            <jats:italic>ERG11<\/jats:italic>\n            ). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            in the absence of the selective drug pressure. In this work, the effect of GOF mutations on\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither\n            <jats:italic>TAC1<\/jats:italic>\n            nor\n            <jats:italic>MRR1<\/jats:italic>\n            GOF mutations had a significant effect on\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            virulence. In contrast, the presence of two hyperactive\n            <jats:italic>UPC2<\/jats:italic>\n            alleles in\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with\n            <jats:italic>UPC2<\/jats:italic>\n            hyperactive alleles was observed in competition experiments with the wild type\n            <jats:italic>in vivo<\/jats:italic>\n            but not\n            <jats:italic>in vitro<\/jats:italic>\n            . Interestingly,\n            <jats:italic>UPC2<\/jats:italic>\n            hyperactivity delayed filamentation of\n            <jats:named-content content-type=\"genus-species\">C. albicans<\/jats:named-content>\n            after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the\n            <jats:italic>UPC2<\/jats:italic>\n            GOF mutation with another hyperactive TF did not compensate for the negative effect of\n            <jats:italic>UPC2<\/jats:italic>\n            on virulence. In conclusion, among the major TFs involved in azole resistance, only\n            <jats:italic>UPC2<\/jats:italic>\n            had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.\n          <\/jats:p>","DOI":"10.1128\/ec.00245-13","type":"journal-article","created":{"date-parts":[[2013,11,15]],"date-time":"2013-11-15T23:29:45Z","timestamp":1384558185000},"page":"127-142","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":83,"title":["Distinct Roles of Candida albicans Drug Resistance Transcription Factors\n            <i>TAC1<\/i>\n            ,\n            <i>MRR1<\/i>\n            , and\n            <i>UPC2<\/i>\n            in Virulence"],"prefix":"10.1128","volume":"13","author":[{"given":"Andrea","family":"Lohberger","sequence":"first","affiliation":[{"name":"Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix T.","family":"Coste","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Sanglard","sequence":"additional","affiliation":[{"name":"Institute of Microbiology, University Hospital Lausanne and University Hospital Center, Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Candida and candidiasis","author":"Calderone RA","year":"2002","unstructured":"CalderoneRA (ed). 2002. 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