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These agents disrupt fungal membranes through ergosterol binding, but how structural differences between the three polyenes influence subcellular distribution, and whether such distribution is linked to resistance, remains uncharacterized. To investigate these relationships, we developed fluorescent probes from each clinically used polyene by conjugating a common fluorophore to a conserved functional group, preserving the amphoteric nature and ergosterol\u2010dependent antifungal activity of the parent drug while enabling live\u2010cell imaging. This unified design allowed direct comparison of localization and trafficking across\n                    <jats:italic>Candida<\/jats:italic>\n                    species, including sterol biosynthesis mutants with a high level of polyene resistance. The probes revealed structure\u2010specific distribution patterns, with resistant strains showing enhanced accumulation within the vacuole lumen for all three polyenes. These findings suggest that vacuolar sequestration contributes to polyene resistance and may represent an unrecognized aspect of the fungal stress response. More broadly, this work provides the first direct visual evidence that polyene structure dictates subcellular distribution patterns in fungal cells.\n                  <\/jats:p>","DOI":"10.1002\/anie.202521135","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T07:35:58Z","timestamp":1763451358000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Fluorescent Probes Derived from the Polyene Class of Antifungal Drugs Reveal Distinct Localization Patterns and Resistance\u2010Associated Vacuolar Sequestration in\n                    <i>Candida<\/i>\n                    Species"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3063-851X","authenticated-orcid":false,"given":"Melissa","family":"Shbeta","sequence":"first","affiliation":[{"name":"School of Chemistry, Raymond &amp; Beverly Sackler Faculty of Exact Sciences Tel Aviv University  Tel Aviv 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