{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T06:48:36Z","timestamp":1793515716391,"version":"4.5.0"},"reference-count":31,"publisher":"Microbiology Society","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001602","name":"Science Foundation Ireland","doi-asserted-by":"crossref","award":["19\/FFP\/6422"],"award-info":[{"award-number":["19\/FFP\/6422"]}],"id":[{"id":"10.13039\/501100001602","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,1]]},"abstract":"<jats:p>\n                  <jats:italic>Candida albicans<\/jats:italic> is an opportunistic fungal pathogen associated with superficial and systemic infections in humans. Azole antifungal resistance in <jats:italic>C. albicans<\/jats:italic> is of clinical concern, and both oral and systemic <jats:italic>Candida<\/jats:italic> infections can be difficult to treat due to the lack of alternative antifungal drugs. Expression of a hyperactive form of the transcription factor Tac1 is a major contributor to azole resistance in <jats:italic>C. albicans<\/jats:italic> isolates resulting in the increased expression of the azole efflux pump Cdr1. In this study, we investigated whether the Mediator tail component Med2, encoded by the expanded (n=14) <jats:italic>TLO<\/jats:italic> gene family of <jats:italic>C. albicans<\/jats:italic>, was required for Tac1 activity. A homozygous <jats:italic>TAC1-5<\/jats:italic> gain-of-function point mutation was introduced into WT, <jats:italic>tlo<\/jats:italic>\u0394 and <jats:italic>med3<\/jats:italic>\u0394 strains of <jats:italic>C. albicans<\/jats:italic> which enables them to express hyperactive Tac1. qRT-PCR analysis revealed that <jats:italic>tlo<\/jats:italic>\u0394-<jats:italic>TAC1-5<\/jats:italic> had reduced basal and fluphenazine-induced <jats:italic>CDR1<\/jats:italic> expression relative to WT-<jats:italic>TAC1-5<\/jats:italic> strains and exhibited reduced levels of resistance to fluconazole and terbinafine. Individual copies of representatives from each of the alpha, beta and gamma <jats:italic>TLO<\/jats:italic> clades were reintroduced into <jats:italic>tlo<\/jats:italic>\u0394-<jats:italic>TAC1-5<\/jats:italic> to investigate their ability to restore Tac1-activated resistance. These studies show that alpha and beta <jats:italic>TLO<\/jats:italic> genes could restore fluconazole resistance in the <jats:italic>tlo<\/jats:italic>\u0394-<jats:italic>TAC1-5<\/jats:italic> background, whereas gamma clade genes did not result in any detectable phenotypic complementation. Transcript profiling showed that reintroduction of <jats:italic>TLO<\/jats:italic>\u03b1<jats:italic>1<\/jats:italic> led to increased expression of <jats:italic>TAC1-5<\/jats:italic>-activated genes such as <jats:italic>CDR1<\/jats:italic>. Further analysis using ChIP-qPCR revealed that Tlo\u03b11 localizes to the drug response element which is the site where Tac1 binds to the <jats:italic>CDR1<\/jats:italic> promoter. These data have identified that the <jats:italic>TLO<\/jats:italic> gene family is required for the expression of Tac1-mediated fluconazole resistance. However, this effect is confined to members of the alpha and beta, but not the gamma, <jats:italic>TLO<\/jats:italic> clades.<\/jats:p>","DOI":"10.1099\/mic.0.001594","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T16:15:56Z","timestamp":1756743356000},"source":"Crossref","is-referenced-by-count":2,"title":["Fluconazole resistance and CDR1 expression in Candida albicans mediated by the hyperactive Tac1-5 transcriptional activator requires Tlo proteins"],"prefix":"10.1099","volume":"171","author":[{"given":"Wen Jun","family":"Lim","sequence":"first","affiliation":[{"name":"Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Genetics and Microbiology, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Farrington","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Genetics and Microbiology, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abed Alkarem","family":"Abu Alhaija","sequence":"additional","affiliation":[{"name":"Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair B.","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Microbiology, School of Genetics and Microbiology, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek J.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0469-1788","authenticated-orcid":false,"given":"Gary P.","family":"Moran","sequence":"additional","affiliation":[{"name":"Division of Oral Biosciences, Dublin Dental University Hospital, University of Dublin, Trinity College Dublin, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"crossref","first-page":"549","DOI":"10.2147\/CLEP.S459600","article-title":"Epidemiology of invasive candidiasis","volume":"16","author":"Bays","year":"2024","journal-title":"Clin Epidemiol"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1007\/s10123-018-0014-1"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(24)00042-9"},{"key":"R4","volume-title":"WHO Fungal Priority Pathogens List to Guide Research, 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