biostudies-literatureLogviniuk DIsrael Science FoundationMinisterio de Ciencia e Innovaci?n?la Caixa? Foundation5965-5975https://www.ebi.ac.uk/biostudies/studies/S-EPMC8991007biostudies-literatureUnknown144(13)Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in <i>FKS</i> genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3<i>S</i>,4<i>S</i>-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-rJournal of the American Chemical SocietyBenzylic Dehydroxylation of Echinocandin Antifungal Drugs Restores Efficacy against Resistance Conferred by Mutated Glucan Synthase.PMC8991007PGC2018-099921-B-I00LCF/PR/HR21/00737LCF/PR/GN18/50310010179/19Jaber QZKozer NDobrovetsky RKsiezopolska EGabaldon TFridman MLogviniuk DCarmeli SfalseBenzylic Dehydroxylation of Echinocandin Antifungal Drugs Restores Efficacy against Resistance Conferred by Mutated Glucan Synthase.Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in <i>FKS</i> genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3<i>S</i>,4<i>S</i>-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-r2022-01-01T00:00:00Z2022 Apr2025-04-05T13:24:10.898Z2025-04-05T13:24:10.898ZS-EPMC89910073534798610.1021/jacs.2c00269