Reshaping Echinocandin Antifungal Drugs To Circumvent Glucan Synthase Point‐Mutation‐Mediated Resistance

• Published in: Angewandte Chemie International Edition 2024-02, Vol.63 (9), p.e202314728-n/a
• Main Authors: Jospe‐Kaufman, Moriah, Ben‐Zeev, Efrat, Mottola, Austin, Dukhovny, Anna, Berman, Judith, Carmeli, Shmuel, Fridman, Micha
• Format: Article
• Language: English
• Subjects: Alcohols; Antifungal agents; Antifungal Agents - pharmacology; Antifungals; Cell walls; Dehydration; Drug Resistance, Fungal - genetics; Drugs; Echinocandin Resistance; Echinocandins; Echinocandins - genetics; Echinocandins - pharmacology; Fungicides; Glucan; Glucan Synthase; Glucosyltransferases - genetics; Glucosyltransferases - metabolism; High resistance; Lipids; Microbial Sensitivity Tests; Mutation; Reductive Dehydration; Site- Selective Modifications
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202314728

Echinocandins are a class of antifungal drugs that inhibit the activity of the β‐(1,3)‐glucan synthase complex, which synthesizes fungal cell wall β‐(1,3)‐glucan. Echinocandin resistance is linked to mutations in the FKS gene, which encodes the catalytic subunit of the glucan synthase complex. We present a molecular‐docking‐based 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 Candida pathogens constructed by introducing resistance‐conferring mutations in the FKS 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‐conferring mutation. Strains that have developed resistance to either rezafungin, the most recently clinically approved echinocandin, or its dehydroxylated derivative RZF‐1, exhibit high resistance to rezafungin while demonstrating moderate resistance to RZF‐1. These findings provide valuable insight for combating echinocandin resistance through chemical modifications. A docking‐based model elucidates how echinocandins form a ternary complex with their glucan synthase target and associated membrane lipids. Removing hemiaminal alcohol from echinocandins reduced, and benzylic dehydroxylation improved potency against echinocandin‐resistant yeast. Candida strains exposed to rezafungin or its dehydroxylated derivative, RZF‐1, evolved resistance, with RZF‐1 showing significantly higher potency against these strains.