{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:52:24Z","timestamp":1793145144027,"version":"4.5.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T00:00:00Z","timestamp":1727395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>With the growing population of immunocompromised individuals, opportunistic fungal pathogens pose a global health threat. <jats:italic>Candida<\/jats:italic> species, particularly <jats:italic>C. albicans<\/jats:italic> and non-albicans <jats:italic>Candida<\/jats:italic> species such as <jats:italic>C. glabrata<\/jats:italic>, are the most prevalent pathogenic fungi. Azoles, especially fluconazole, are widely used therapeutic options.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>This study investigates how <jats:italic>C. glabrata<\/jats:italic> adapts to fluconazole, with a focus on understanding the factors regulating fluconazole tolerance and its relationship to resistance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study compared the factors regulating fluconazole tolerance between <jats:italic>C. albicans<\/jats:italic> and <jats:italic>C. glabrata<\/jats:italic>. We analyzed the impact of temperature on fluconazole tolerance, and requirement of calcineurin and Hsp90 for maintenance of fluconazole tolerance. We isolated colonies from edge, inside and outside of inhibition zone in disk diffusion assays. And we exposed <jats:italic>C. glabrata<\/jats:italic> strain to high concentrations of fluconazole and investigated the mutants for development of fluconazole resistance and tolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found temperature modulated tolerance in the opposite way in <jats:italic>C.\u00a0albicans<\/jats:italic> strain YJB-T1891 and <jats:italic>C. glabrata<\/jats:italic> strain CG4. Calcineurin and Hsp90 were required for maintenance of fluconazole tolerance in both species. Colonies from inside and outside of inhibition zones did not exhibited mutated phenotype, but colonies isolated from edge of inhibition zone exhibited diverse phenotype changes. Moreover, we discovered that high concentrations (16-128 \u03bcg\/mL) of fluconazole induce the simultaneous but parallel development of tolerance and resistance in <jats:italic>C. glabrata<\/jats:italic>, unlike the sole development of tolerance in <jats:italic>C. albicans<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights that while tolerance to fluconazole is a common response in <jats:italic>Candida<\/jats:italic> species, the specific molecular mechanisms and evolutionary pathways that lead to this response vary between species. Our findings emphasize the importance of understanding the regulation of fluconazole tolerance in different <jats:italic>Candida<\/jats:italic> species to develop effective therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2024.1456907","type":"journal-article","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T05:10:35Z","timestamp":1727413835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Parallel evolution of fluconazole resistance and tolerance in Candida glabrata"],"prefix":"10.3389","volume":"14","author":[{"given":"Lijun","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangsheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.diagmicrobio.2012.06.012","article-title":"The PATH (Prospective Antifungal Therapy) Alliance(R) registry and invasive fungal infections: update 2012","volume":"73","author":"Azie","year":"2012","journal-title":"Diagn. 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