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Resistance is often caused by gain\u2010of\u2010function mutations in the transcription factors <jats:styled-content style=\"fixed-case\">Mrr<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">Tac<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">Upc<\/jats:styled-content>2, which result in constitutive overexpression of multidrug efflux pumps and ergosterol biosynthesis genes respectively. It is not known how the permanently changed gene expression program in resistant strains affects their fitness in the absence of drug selection pressure. We have systematically investigated the effects of activating mutations in <jats:styled-content style=\"fixed-case\">Mrr<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">Tac<\/jats:styled-content>1 and <jats:styled-content style=\"fixed-case\">Upc<\/jats:styled-content>2, individually and in all possible combinations, on the degree of fluconazole resistance and on the fitness of <jats:italic><jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>.\u2009albicans<\/jats:italic> in an isogenic strain background. All combinations of different resistance mechanisms resulted in a stepwise increase in drug resistance, culminating in 500\u2010fold increased fluconazole resistance in strains possessing mutations in the three transcription factors and an additional resistance mutation in the drug target enzyme <jats:styled-content style=\"fixed-case\">Erg<\/jats:styled-content>11. The acquisition of resistance mutations was associated with reduced fitness under non\u2010selective conditions <jats:italic>in vitro<\/jats:italic> as well as <jats:italic>in vivo<\/jats:italic> during colonization of a mammalian host. Therefore, without compensatory mutations, the inability to appropriately regulate gene expression results in a loss of competitive fitness of drug\u2010resistant <jats:italic><jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>.\u2009albicans<\/jats:italic> strains.<\/jats:p>","DOI":"10.1111\/j.1365-2958.2012.08210.x","type":"journal-article","created":{"date-parts":[[2012,8,28]],"date-time":"2012-08-28T07:25:22Z","timestamp":1346138722000},"page":"539-556","source":"Crossref","is-referenced-by-count":84,"title":["The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in <i><scp>C<\/scp>andida albicans<\/i>"],"prefix":"10.1111","volume":"86","author":[{"given":"Christoph","family":"Sasse","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Molekulare Infektionsbiologie Universit\u00e4t W\u00fcrzburg  W\u00fcrzburg 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