Benzylic Dehydroxylation of Echinocandin antifungal drugs restores efficacy against resistance conferred by mutated Glucan Synthase
| Autor: | Dana Logviniuk, Qais Z. Jaber, Roman Dobrovetsky, Noga Kozer, Ewa Ksiezopolska, Toni Gabaldón, Shmuel Carmeli, Micha Fridman |
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| Přispěvatelé: | Barcelona Supercomputing Center |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC]
Drug-resistant fungal pathogens Antifungal Agents General Chemistry Microbial Sensitivity Tests Biochemistry Catalysis Fungal Proteins Echinocandins Colloid and Surface Chemistry Drug Resistance Fungal Glucosyltransferases Mutation Candidiasi Humans Tyrosine Fungal diseases Antifungal agents Fungal proteins Fungal pathogens FKS genes |
| Zdroj: | UPCommons. Portal del coneixement obert de la UPC Universitat Politècnica de Catalunya (UPC) |
| Popis: | 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 FKS 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 3S,4S-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-resistant Candida strains. The dehydroxylated compounds did not significantly affect the viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistant Candida strains, which contain mutations in the FKS1 and/or FKS2 genes of the parental strains, identified amino acids of the Fks proteins that are likely to reside in proximity to the l-homotyrosine residue of the bound drug. This study describes the first example of a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal of antifungal drugs, against resistant fungal pathogens. The authors thank J. Berman and D. Perlin for providing Candida strains. This work was supported by the Israel Science Foundation Grant 179/19 (Micha Fridman). TG acknowledges support from the Spanish Ministry of Science and Innovation for grant PGC2018-099921-B-I00 and from the “la Caixa” Foundation under the agreements LCF/PR/GN18/50310010 and LCF/PR/HR21/00737. They also thank E. Ainbinder. O. Singer, and Y. Fried from the Stem Cell Unit of Life Science Core Facilities, the Weizmann Institute of Science. They especially thank H. Barr, head of HTS and Medicinal Chemistry Units at the Maurice and Vivienne Wohl Institute for Drug Discovery, The Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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