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
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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