Target Identification and Mechanism of Action of Picolinamide and Benzamide Chemotypes with Antifungal Properties
Autor: | Thomas Aust, Fulvia Bono, Herbert Waldmann, Ralph Riedl, Sasikala Thavam, Anna-Lena Keller, Francesca Perruccio, Danish Khan, Verena Pries, Slava Ziegler, Gabriel Schaaf, Vytas A. Bankaitis, Ashutosh Tripathi, Christina Nöcker, Michael Fitz, Zebin Hong, Philipp Johnen, Dominic Hoepfner, Ireos Filipuzzi |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Antifungal Agents Saccharomyces cerevisiae Proteins Chemical structure 030106 microbiology Clinical Biochemistry Saccharomyces cerevisiae Microbial Sensitivity Tests Biology Molecular Dynamics Simulation Crystallography X-Ray Biochemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Drug Resistance Fungal Drug Discovery Candida albicans medicine Chemogenomics Amino Acid Sequence Phospholipid Transfer Proteins Benzamide Mode of action Picolinic Acids Molecular Biology Pharmacology Binding Sites Phosphatidylcholine transfer protein biology.organism_classification Amides Protein Structure Tertiary 030104 developmental biology Aspergillus Mechanism of action Drug development chemistry Benzamides Mutagenesis Site-Directed Molecular Medicine medicine.symptom Sequence Alignment |
Zdroj: | Cell chemical biology. 25(3) |
ISSN: | 2451-9448 |
Popis: | Invasive fungal infections are accompanied by high mortality rates that range up to 90%. At present, only three different compound classes are available for use in the clinic, and these often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents. Herein, we report the identification of chemically versatile benzamide and picolinamide scaffolds with antifungal properties. Chemogenomic profiling and biochemical assays with purified protein identified Sec14p, the major phosphatidylinositol/phosphatidylcholine transfer protein in Saccharomyces cerevisiae, as the sole essential target for these compounds. A functional variomics screen identified resistance-conferring residues that localized to the lipid-binding pocket of Sec14p. Determination of the X-ray co-crystal structure of a Sec14p-compound complex confirmed binding in this cavity and rationalized both the resistance-conferring residues and the observed structure-activity relationships. Taken together, these findings open new avenues for rational compound optimization and development of novel antifungal agents. |
Databáze: | OpenAIRE |
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