{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T05:00:31Z","timestamp":1775624431160,"version":"3.50.1"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T00:00:00Z","timestamp":1652054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FCT\u2014Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["UIDB\/04565\/2020"],"award-info":[{"award-number":["UIDB\/04565\/2020"]}]},{"name":"Research Unit Institute for Bioengineering and Biosciences\u2014iBB","award":["LA\/P\/0140\/2020"],"award-info":[{"award-number":["LA\/P\/0140\/2020"]}]},{"name":"Associate Laboratory Institute for Health and Bioeconomy\u2014i4HB"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The pathogenic yeast Candida glabrata is intrinsically resilient to azoles and rapidly acquires resistance to these antifungals, in vitro and in vivo. In most cases azole-resistant C. glabrata clinical strains encode hyperactive CgPdr1 variants, however, resistant strains encoding wild-type CgPDR1 alleles have also been isolated, although remaining to be disclosed the underlying resistance mechanism. In this study, we scrutinized the mechanisms underlying resistance to azoles of 8 resistant clinical C. glabrata strains, identified along the course of epidemiological surveys undertaken in Portugal. Seven of the strains were found to encode CgPdr1 gain-of-function variants (I392M, E555K, G558C, and I803T) with the substitutions I392M and I803T being herein characterized as hyper-activating mutations for the first time. While cells expressing the wild-type CgPDR1 allele required the mediator subunit Gal11A to enhance tolerance to fluconazole, this was dispensable for cells expressing the I803T variant indicating that the CgPdr1 interactome is shaped by different gain-of-function substitutions. Genomic and transcriptomic profiling of the sole azole-resistant C. glabrata isolate encoding a wild-type CgPDR1 allele (ISTB218) revealed that under fluconazole stress this strain over-expresses various genes described to provide protection against this antifungal, while also showing reduced expression of genes described to increase sensitivity to these drugs. The overall role in driving the azole-resistance phenotype of the ISTB218 C. glabrata isolate played by these changes in the transcriptome and genome of the ISTB218 isolate are discussed shedding light into mechanisms of resistance that go beyond the CgPdr1-signalling pathway and that may alone, or in combination, pave the way for the acquisition of resistance to azoles in vivo.<\/jats:p>","DOI":"10.1093\/g3journal\/jkac110","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T12:30:19Z","timestamp":1652099419000},"source":"Crossref","is-referenced-by-count":18,"title":["Disclosing azole resistance mechanisms in resistant <i>Candida glabrata<\/i> strains encoding wild-type or gain-of-function <i>CgPDR1<\/i> alleles through comparative genomics and transcriptomics"],"prefix":"10.1093","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4867-8975","authenticated-orcid":false,"given":"Sara B","family":"Salazar","sequence":"first","affiliation":[{"name":"iBB, Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico\u2014Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisboa 1049-001, Portugal"}]},{"given":"Maria Joana F","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"iBB, Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico\u2014Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisboa 1049-001, Portugal"}]},{"given":"Danielle","family":"Sotti-Novais","sequence":"additional","affiliation":[{"name":"iBB, Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico\u2014Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisboa 1049-001, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-7461","authenticated-orcid":false,"given":"Ana R","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro , Aveiro 3810, Portugal"}]},{"given":"Maria M","family":"Lopes","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia e Imunologia, Faculdade de Farm\u00e1cia da Universidade de Lisboa , Lisboa 1649-003, Portugal"}]},{"given":"Teresa","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Microbiologia, Hospital Dona Estef\u00e2nia (Centro Hospitalar Universit\u00e1rio Lisboa Central) , Lisboa 1169-045, Portugal"}]},{"given":"Vit\u00f3ria","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Se\u00e7\u00e3o de Microbiologia, Laborat\u00f3rio SYNLAB\u2014Lisboa, Grupo SYNLAB Portugal , Lisboa 1070-061, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9112-265X","authenticated-orcid":false,"given":"F\u00e1bio","family":"Fernandes","sequence":"additional","affiliation":[{"name":"iBB, Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico\u2014Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisboa 1049-001, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7556-0385","authenticated-orcid":false,"given":"Nuno P","family":"Mira","sequence":"additional","affiliation":[{"name":"iBB, Institute for Bioengineering and Biosciences, Instituto Superior T\u00e9cnico\u2014Department of Bioengineering, Universidade de Lisboa , Lisboa 1049-001, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy at Instituto Superior T\u00e9cnico, Universidade de Lisboa , Lisboa 1049-001, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2022,5,9]]},"reference":[{"issue":"7","key":"2024042309343066900_jkac110-B1","doi-asserted-by":"crossref","first-page":"e02503-18","DOI":"10.1128\/AAC.02503-18","article-title":"Low level of antifungal resistance in Iranian isolates of Candida glabrata recovered from blood samples in a multicenter study from 2015 to 2018 and potential prognostic values of genotyping and sequencing of PDR1","volume":"63","author":"Arastehfar","year":"2019","journal-title":"Antimicrob Agents Chemother"},{"issue":"9","key":"2024042309343066900_jkac110-B2","doi-asserted-by":"crossref","first-page":"676.e7","DOI":"10.1016\/j.cmi.2017.03.014","article-title":"Identification of genetic markers of resistance to echinocandins, 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