{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:00:04Z","timestamp":1790244004523,"version":"4.1.0"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Mundipharma to investigate antifungal resistance mechanisms in yeasts"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Candida parapsilosis is a leading cause of invasive candidiasis globally, with rising reports of fluconazole resistance threatening its clinical management. Among the mechanisms involved, gain-of-function mutations in the MRR1 gene have emerged as key drivers of antifungal resistance. We aimed to investigate a novel amino acid substitution (G982E) in the Mrr1 zinc cluster transcription factor, identified in a fluconazole-resistant C. parapsilosis isolate from a patient exposed to fluconazole.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using CRISPR-Cas9 genome editing, we introduced the G982E variant into two fluconazole-susceptible C. parapsilosis genetic backgrounds. The antifungal susceptibility of the engineered mutants was assessed in vitro against a broad panel of systemic antifungal agents. A Galleria mellonella infection model was also used to evaluate the impact of the G982E variant on antifungal treatment efficacy and virulence in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Acquisition of the G982E substitution dramatically altered the antifungal susceptibility profile, particularly for fluconazole for which the minimum inhibitory concentration (MIC) increased to &amp;gt;256 \u00b5g\/mL. However, the magnitude of the MIC increase varied by azole, with the greatest increase seen for fluconazole (&amp;gt;9\u201310 log-fold), followed by voriconazole (5 log-fold), isavuconazole (3 log-fold), but also flucytosine (1.5 log-fold). In contrast, susceptibility to posaconazole remained largely unchanged. In vivo, this new variant conferred fluconazole treatment failure but was associated with a significant reduction in virulence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The G982E is a novel Mrr1 gain-of-function mutation driving high-level fluconazole resistance in C. parapsilosis. These findings reinforce the central role of Mrr1 in antifungal resistance, underscore the functional diversity of its mutational landscape, with potential implications for fungal fitness and transcriptional regulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/mmy\/myag094","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:22:29Z","timestamp":1788520949000},"source":"Crossref","is-referenced-by-count":0,"title":["A new\n                    <i>MRR1<\/i>\n                    gain-of-function mutation involved in cross-resistance to antifungal agents in the fungal priority pathogen\n                    <i>Candida parapsilosis<\/i>"],"prefix":"10.1093","volume":"64","author":[{"given":"Manon","family":"Cadeau","sequence":"first","affiliation":[{"name":"CHU Nantes, Cibles et M\u00e9dicaments des Infections et de l\u2019Immunit\u00e9, IICiMed, UR1155, Nantes Universit\u00e9 , 44000 Nantes 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