{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:46:52Z","timestamp":1790887612461,"version":"4.1.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["(81402978"],"award-info":[{"award-number":["(81402978"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023MH227"],"award-info":[{"award-number":["ZR2023MH227"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The emergence of tolerance to antifungal agents in\n                      <jats:italic>Candida albicans<\/jats:italic>\n                      complicates the treatment of fungal infections. Understanding the mechanisms underlying this tolerance is crucial for developing effective therapeutic strategies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This study aims to elucidate the genetic and molecular basis of ketoconazole tolerance in\n                      <jats:italic>C. albicans<\/jats:italic>\n                      , focusing on the roles of chromosomal aneuploidy, Hsp90, and calcineurin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The wild-type\n                      <jats:italic>C. albicans<\/jats:italic>\n                      strain SC5314 was exposed to increasing concentrations of ketoconazole (0.015\u201332\u2009\u03bcg\/mL) to select for tolerant adaptors. Disk diffusion and spot assays were used to assess tolerance. Whole-genome sequencing identified chromosomal changes in the adaptors. The roles of Hsp90 and calcineurin in maintaining and developing ketoconazole tolerance were investigated using specific inhibitors and knockout strains.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Adaptors exhibited tolerance to ketoconazole concentrations up to 16\u2009\u03bcg\/mL, a significant increase from the parent strain\u2019s inhibition at 0.015\u2009\u03bcg\/mL. All tolerant adaptors showed amplification of chromosome R, with 29 adaptors having trisomy and one having tetrasomy. This aneuploidy was unstable, reverting to euploidy and losing tolerance in drug-free conditions. Both Hsp90 and calcineurin were essential for maintaining and developing ketoconazole tolerance. Inhibition of these proteins resulted in loss of tolerance. The efflux gene\n                      <jats:italic>CDR1<\/jats:italic>\n                      was not required for the development of tolerance. Chromosome R trisomy and tetrasomy induce cross-tolerance to other azole antifungal agents, including clotrimazole and miconazole, but not to other antifungal classes, such as echinocandins and pyrimidines, exemplified by caspofungin and 5-flucytosine.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Ketoconazole tolerance in\n                      <jats:italic>C. albicans<\/jats:italic>\n                      is mediated by chromosomal aneuploidy, specifically chromosome R amplification, and requires Hsp90 and calcineurin. These findings highlight potential targets for therapeutic intervention to combat antifungal tolerance and improve treatment outcomes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2024.1450557","type":"journal-article","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:56:48Z","timestamp":1722301008000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Ketoconazole induces reversible antifungal drug tolerance mediated by trisomy of chromosome R in Candida albicans"],"prefix":"10.3389","volume":"15","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":"Liangsheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13073-014-0100-8","article-title":"YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens","volume":"6","author":"Abbey","year":"2014","journal-title":"Genome Med."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1080\/13693780500138971","article-title":"An update on antifungal targets and mechanisms of resistance in Candida albicans","volume":"43","author":"Akins","year":"2005","journal-title":"Med. 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