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Distinguished by its remarkable resilience to environmental stressors,\n              <jats:italic>C. glabrata<\/jats:italic>\n              exhibits intrinsic tolerance to azoles and a high propensity to swiftly develop azole resistance during treatment. The molecular mechanism for the high tolerance is not fully understood. In this work, we investigated the possible role of trehalose in this tolerance. We generated mutants in the\n              <jats:italic>C. glabrata TPS1<\/jats:italic>\n              ,\n              <jats:italic>TPS2<\/jats:italic>\n              , and\n              <jats:italic>NTH1<\/jats:italic>\n              genes, encoding trehalose 6-phosphate synthase (Tps1), trehalose 6-phosphate phosphatase (Tps2), and neutral trehalase (Nth1), respectively. As expected, the\n              <jats:italic>tps1\u2206<\/jats:italic>\n              strain cannot grow on glucose. The\n              <jats:italic>tps2<\/jats:italic>\n              \u2206 strain demonstrated diminished trehalose accumulation and very high levels of trehalose 6-phosphate (T6P), the biosynthetic intermediate, in comparison to the wild-type (WT) strain. Whereas these higher T6P levels did not affect growth, the lower trehalose levels clearly resulted in lower environmental stress tolerance and a lower susceptibility to fluconazole. More interestingly, the\n              <jats:italic>tps2\u2206<\/jats:italic>\n              strain completely lost tolerance to fluconazole, characterized by the absence of slow growth at supra-MIC concentrations of this drug. All these phenotypes are reversed in the\n              <jats:italic>nth1<\/jats:italic>\n              \u2206 strain, which accumulates high levels of trehalose. Our findings underscore the role of trehalose in enabling tolerance toward fluconazole in\n              <jats:italic>C. glabrata<\/jats:italic>\n              . We further show that the change in tolerance is a result of the effect that trehalose has on the sterol pattern in the cell.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01349-24","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T14:00:16Z","timestamp":1737727216000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["The stress-protectant molecule trehalose mediates fluconazole tolerance in\n            <i>Candida glabrata<\/i>"],"prefix":"10.1128","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4242-1623","authenticated-orcid":false,"given":"Qingjuan","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-8860","authenticated-orcid":false,"given":"Stefanie","family":"Wijnants","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Feil","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Molecular Plant Physiology","place":["Potsdam-Golm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8562-8029","authenticated-orcid":false,"given":"Wouter","family":"Van Genechten","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudy","family":"Vergauwen","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odessa","family":"Van Goethem","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"Lunn","sequence":"additional","affiliation":[{"name":"Max Planck Institute of Molecular Plant Physiology","place":["Potsdam-Golm, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mieke","family":"Van Ende","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1542-897X","authenticated-orcid":true,"given":"Patrick","family":"Van Dijck","sequence":"additional","affiliation":[{"name":"Department of Biology, Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KU Leuven","place":["Leuven, Belgium"]},{"name":"Leuven One Health Institute, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms7020039"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/jof7080667"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/1469-0691.12539"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12281-023-00455-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2018.26"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S118892"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgar.2022.05.004"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics9120877"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.143.3.1384-1394.1980"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389203724666230606154719"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2021.10.003"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)77303-7"},{"key":"e_1_3_3_14_2","first-page":"447","article-title":"Investigation of the relationship between sst1 and fdp mutations in yeast and their effect on trehalose synthesis","volume":"18","author":"Charlab R","year":"1985","unstructured":"Charlab R, Oliveira DE, Panek AD. 1985. 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