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Echinocandin resistance is linked to mutations in the <jats:italic>FKS<\/jats:italic> gene, which encodes the catalytic subunit of the glucan synthase complex. We present a molecular\u2010docking\u2010based model that provides insight into how echinocandins interact with the target Fks protein: echinocandins form a ternary complex with both Fks and membrane lipids. We used reductive dehydration of alcohols to generate dehydroxylated echinocandin derivatives and evaluated their potency against a panel of <jats:italic>Candida<\/jats:italic> pathogens constructed by introducing resistance\u2010conferring mutations in the <jats:italic>FKS<\/jats:italic> gene. We found that removing the hemiaminal alcohol, which drives significant conformational alterations in the modified echinocandins, reduced their efficacy. Conversely, eliminating the benzylic alcohol of echinocandins enhanced potency by up to two orders of magnitude, in a manner dependent upon the resistance\u2010conferring mutation. Strains that have developed resistance to either rezafungin, the most recently clinically approved echinocandin, or its dehydroxylated derivative RZF\u20101, exhibit high resistance to rezafungin while demonstrating moderate resistance to RZF\u20101. These findings provide valuable insight for combating echinocandin resistance through chemical modifications.<\/jats:p>","DOI":"10.1002\/anie.202314728","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T22:03:55Z","timestamp":1704060235000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Reshaping Echinocandin Antifungal Drugs To Circumvent Glucan Synthase Point\u2010Mutation\u2010Mediated Resistance"],"prefix":"10.1002","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9171-7686","authenticated-orcid":false,"given":"Moriah","family":"Jospe\u2010Kaufman","sequence":"first","affiliation":[{"name":"School of Chemistry Raymond &amp; Beverly Sackler Faculty of Exact Sciences Tel Aviv University  6997801 Tel Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9954-3248","authenticated-orcid":false,"given":"Efrat","family":"Ben\u2010Zeev","sequence":"additional","affiliation":[{"name":"The Whol Drug Discovery institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine Weizmann Institute of Science  7610001 Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4437-9249","authenticated-orcid":false,"given":"Austin","family":"Mottola","sequence":"additional","affiliation":[{"name":"Shmunis School of Biomedical and Cancer Research George\u2005S. 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