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Here we show that the azole-induced synthesis of fungicidal cell wall carbohydrate patches in the pathogenic mold\n                    <jats:italic>Aspergillus fumigatus<\/jats:italic>\n                    strictly correlates with the accumulation of the CYP51 substrate eburicol. A lack of other essential ergosterol biosynthesis enzymes, such as sterol C24-methyltransferase (Erg6A), squalene synthase (Erg9) or squalene epoxidase (Erg1) does not trigger comparable cell wall alterations. Partial repression of Erg6A, which converts lanosterol into eburicol, increases azole resistance. The sterol C5-desaturase (ERG3)-dependent conversion of eburicol into 14-methylergosta-8,24(28)-dien-3\u03b2,6\u03b1-diol, the \u201ctoxic diol\u201d responsible for the fungistatic activity against yeasts, is not required for the fungicidal effects in\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    . While ERG3-lacking yeasts are azole resistant, ERG3-lacking\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    becomes more susceptible. Mutants lacking mitochondrial complex III functionality, which are much less effectively killed, but strongly inhibited in growth by azoles, convert eburicol more efficiently into the supposedly \u201ctoxic diol\u201d. We propose that the mode of action of azoles against\n                    <jats:italic>A. fumigatus<\/jats:italic>\n                    relies on accumulation of eburicol which exerts fungicidal effects by triggering cell wall carbohydrate patch formation.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-50609-1","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T20:03:07Z","timestamp":1722024187000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Toxic eburicol accumulation drives the antifungal activity of azoles against Aspergillus fumigatus"],"prefix":"10.1038","volume":"15","author":[{"given":"Hesham","family":"Elsaman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9337-6232","authenticated-orcid":false,"given":"Evgeny","family":"Golubtsov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Brazil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9841-141X","authenticated-orcid":false,"given":"Natanya","family":"Ng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6947-2487","authenticated-orcid":false,"given":"Isabel","family":"Klugherz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2212-1511","authenticated-orcid":false,"given":"Ronny","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Dichtl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1163-2527","authenticated-orcid":false,"given":"Christoph","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5952-9422","authenticated-orcid":false,"given":"Johannes","family":"Wagener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"50609_CR1","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1126\/science.aap7999","volume":"360","author":"MC Fisher","year":"2018","unstructured":"Fisher, M. 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