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

Autor: Jospe-Kaufman M; School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel., Ben-Zeev E; The Whol Drug Discovery institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, 7610001, Rehovot, Israel., Mottola A; Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel., Dukhovny A; Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel., Berman J; Shmunis School of Biomedical and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel., Carmeli S; School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel., Fridman M; School of Chemistry, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, 6997801, Tel Aviv, Israel.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Feb 26; Vol. 63 (9), pp. e202314728. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1002/anie.202314728
Abstrakt: 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.
(© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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