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The transcription factor Crz1, a key regulator of cellular stress responses and virulence, is an attractive therapeutic target because this protein is absent in human cells. Here, we used a CRISPR-Cas9 approach to generate isogenic<jats:italic>crz1<\/jats:italic>\u0394 strains in two clinical isolates of caspofungin-resistant<jats:italic>C<\/jats:italic>.<jats:italic>glabrata<\/jats:italic>to analyze the role of this transcription factor in susceptibility to echinocandins, stress tolerance, biofilm formation, and pathogenicity in both non-vertebrate (<jats:italic>Galleria mellonella<\/jats:italic>) and vertebrate (mice) models of candidiasis. In these clinical isolates,<jats:italic>CRZ1<\/jats:italic>disruption restores the susceptibility to echinocandins in both<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>models, and affects their oxidative stress response, biofilm formation, cell size, and pathogenicity. These results strongly suggest that Crz1 inhibitors may play an important role in the development of novel therapeutic agents against fungal infections considering the emergence of antifungal resistance and the low number of available antifungal drugs.<\/jats:p>","DOI":"10.1371\/journal.pone.0265777","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T17:27:00Z","timestamp":1647624420000},"page":"e0265777","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["CRISPR-Cas9 approach confirms Calcineurin-responsive zinc finger 1 (Crz1) transcription factor as a promising therapeutic target in echinocandin-resistant Candida glabrata"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0743-6857","authenticated-orcid":true,"given":"Andres","family":"Ceballos-Garzon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas","family":"Pla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1759-5106","authenticated-orcid":true,"given":"Fabrice","family":"Pagniez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5796-5979","authenticated-orcid":true,"given":"Daniela","family":"Amado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-1173","authenticated-orcid":true,"given":"Carlos 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