TY - JOUR
T1 - Reshaping Echinocandin Antifungal Drugs To Circumvent Glucan Synthase Point-Mutation-Mediated Resistance
AU - Jospe-Kaufman, Moriah
AU - Ben-Zeev, Efrat
AU - Mottola, Austin
AU - Dukhovny, Anna
AU - Berman, Judith
AU - Carmeli, Shmuel
AU - Fridman, Micha
N1 - Publisher Copyright:
© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.
PY - 2024/2/26
Y1 - 2024/2/26
N2 - 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.
AB - 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.
KW - Antifungals
KW - Echinocandin Resistance
KW - Glucan Synthase
KW - Reductive Dehydration
KW - Site- Selective Modifications
UR - http://www.scopus.com/inward/record.url?scp=85182425855&partnerID=8YFLogxK
U2 - 10.1002/anie.202314728
DO - 10.1002/anie.202314728
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C2 - 38161189
AN - SCOPUS:85182425855
SN - 1433-7851
VL - 63
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 9
M1 - e202314728
ER -