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

Moriah Jospe-Kaufman, Efrat Ben-Zeev, Austin Mottola, Anna Dukhovny, Judith Berman, Shmuel Carmeli, Micha Fridman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere202314728
JournalAngewandte Chemie - International Edition
Volume63
Issue number9
DOIs
StatePublished - 26 Feb 2024

Funding

FundersFunder number
Israel Ministry of Science, Technology & Space for the Levi Eshkol Scholarship315461
Teva Pharmaceutical Industries
European Research Council
Israel Science Foundation179/19
Ministry of Health, State of Israel3–18841
Horizon 2020951475

    Keywords

    • Antifungals
    • Echinocandin Resistance
    • Glucan Synthase
    • Reductive Dehydration
    • Site- Selective Modifications

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