{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T06:14:50Z","timestamp":1767852890756,"version":"3.49.0"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The basal fungus\n                      <jats:italic>Mucor lusitanicus<\/jats:italic>\n                      (\n                      <jats:italic>Mlu<\/jats:italic>\n                      ) is a cause of mucormycosis, with limited treatment options due to intrinsic resistance to short-tailed azoles (fluconazole, voriconazole) and echinocandins.\n                      <jats:italic>In silico<\/jats:italic>\n                      analysis identified amino-acid-substitutions Y129F and V293A in the substrate-binding pocket of sterol-14\u03b1-demethylase (Cyp51, Erg11) isoform F5 as potential resistance mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This hypothesis has been experimentally tested for\n                      <jats:italic>M. lusitanicus<\/jats:italic>\n                      by expressing its Cyp51 isoforms (MluCyp51-F1, MluCyp51-F5) and modified MluCyp51-F5 variants (F129Y, A293V, F129Y A293V) with\/without their cognate NADPH-cytochrome-P450-reductase (MluCPR) in\n                      <jats:italic>Saccharomyces cerevisiae<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Strains expressing MluCyp51 isoforms +\/\u2212 MluCPR showed expression levels of 38\u201369% compared to an overexpressed Erg11 control. Susceptibility assays confirmed that MluCyp51-F5 confers intrinsic resistance to short-tailed azoles, while substitutions F129Y, A293V, or both restored susceptibility. Growth- and susceptibility-assays revealed that the MluCyp51-F1\u202f+\u202fCPR construct had a voriconazole MIC of 0.5\u202f\u03bcM, while MluCyp51-F5\u202f+\u202fCPR had a MIC of 11.5\u202f\u03bcM, with no changes in growth rate or ergosterol composition at 1.0\u202f\u03bcM voriconazole. Susceptibility to long-tailed azoles (e.g., posaconazole) remained unchanged for both isoforms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      These findings demonstrate the functional expression of MluCyp51-F1 and MluCyp51-F5 isoforms in a phylogenetically distant host and confirm that conserved substitutions Y129F and V293A in MluCyp51-F5 confer intrinsic resistance to short-tailed azoles in\n                      <jats:italic>M. lusitanicus<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2025.1702408","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T06:34:25Z","timestamp":1764138865000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Intrinsic resistance to short-tailed azoles in the basal fungus Mucor lusitanicus: functional analysis of Cyp51 isoforms and amino acid substitutions"],"prefix":"10.3389","volume":"16","author":[{"given":"K.","family":"Rosam","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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