{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:59:10Z","timestamp":1791273550014,"version":"4.1.0"},"reference-count":66,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2014,8,1]],"date-time":"2014-08-01T00:00:00Z","timestamp":1406851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,8]]},"abstract":"ABSTRACT<\/jats:title>\n \n Candida glabrata<\/jats:named-content>\n , the second most common cause of\n Candida<\/jats:named-content>\n infections, is associated with high rates of mortality and often exhibits resistance to the azole class of antifungal agents. Upc2 and Ecm22 in\n Saccharomyces cerevisiae<\/jats:named-content>\n and Upc2 in\n Candida albicans<\/jats:named-content>\n are the transcriptional regulators of\n ERG11<\/jats:italic>\n , the gene encoding the target of azoles in the ergosterol biosynthesis pathway. Recently two homologs for these transcription factors,\n UPC2A<\/jats:italic>\n and\n UPC2B<\/jats:italic>\n , were identified in\n C. glabrata<\/jats:named-content>\n . One of these,\n UPC2A<\/jats:italic>\n , was shown to influence azole susceptibility. We hypothesized that due to the global role for Upc2 in sterol biosynthesis in\n S. cerevisiae<\/jats:named-content>\n and\n C. albicans<\/jats:named-content>\n , disruption of\n UPC2A<\/jats:italic>\n would enhance the activity of fluconazole in both azole-susceptible dose-dependent (SDD) and -resistant\n C. glabrata<\/jats:named-content>\n clinical isolates. To test this hypothesis, we constructed mutants with disruptions in\n UPC2A<\/jats:italic>\n and\n UPC2B<\/jats:italic>\n alone and in combination in a matched pair of clinical azole-SDD and -resistant isolates. Disruption of\n UPC2A<\/jats:italic>\n in both the SDD and resistant isolates resulted in increased susceptibility to sterol biosynthesis inhibitors, including a reduction in fluconazole MIC and minimum fungicidal concentration, enhanced azole activity by time-kill analysis, a decrease in ergosterol content, and downregulation of baseline and inducible expression of several sterol biosynthesis genes. Our results indicate that Upc2A is a key regulator of ergosterol biosynthesis and is essential for resistance to sterol biosynthesis inhibitors in\n C. glabrata<\/jats:named-content>\n . Therefore, the\n UPC2A<\/jats:italic>\n pathway may represent a potential cotherapeutic target for enhancing azole activity against this organism.\n <\/jats:p>","DOI":"10.1128\/aac.02217-13","type":"journal-article","created":{"date-parts":[[2014,5,28]],"date-time":"2014-05-28T07:08:08Z","timestamp":1401260888000},"page":"4543-4554","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":60,"title":["UPC2A<\/i>\n Is Required for High-Level Azole Antifungal Resistance in Candida glabrata"],"prefix":"10.1128","volume":"58","author":[{"given":"Sarah G.","family":"Whaley","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA"},{"name":"Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly E.","family":"Caudle","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA"},{"name":"Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John-Paul","family":"Vermitsky","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, L.L.C., Genesis Biotechnology Group, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean G.","family":"Chadwick","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, L.L.C., Genesis Biotechnology Group, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey","family":"Toner","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, L.L.C., Genesis Biotechnology Group, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Barker","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA"},{"name":"Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA"},{"name":"Children's Foundation Research Center at Le Bonheur Children's Medical Center, Memphis, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Gygax","sequence":"additional","affiliation":[{"name":"Femeris Women's Health Research Center, Medical Diagnostic Laboratories, L.L.C., Genesis Biotechnology Group, Hamilton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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