title: Proteomic characterization of Aspergillus fumigatus treated with an antifungal coumarin for identification of novel target molecules of key pathways.
abstract: A synthetic coumarin, N,N,N-triethyl-11-(4-methyl-2-oxo-2H-chromen-7-yloxy)-11-oxoundecan-1-aminium bromide (SCD-1), having potent activity against pathogenic Aspergilli (MIC90 15.62 μg/mL), was investigated to identify its molecular targets in the pathogen. The proteome of Aspergillus fumigatus was developed after treatment with sublethal doses of compound and analyzed. The results demonstrated 143 differentially expressed proteins on treatment with SCD-1. The expression of four proteins, namely cell division control protein, ubiquitin-like activating enzyme, vacuolar ATP synthase catalytic subunit A, and UTP-glucose-1-phosphate uridylyltransferase of A. fumigatus, was completely inhibited, whereas there were 13 newly expressed and 96 overexpressed proteins, mainly belonging to stress pathway. The treatment of A. fumigatus with SCD-1 also led to attenuation of proteins involved in cell replication and other important biosynthetic processes, including riboflavin biosynthesis, which has been pathogen-specific. In addition to key enzymatic players and antioxidants, nine hypothetical proteins were also identified, seven of which have been novel, being described for the first time. As no cellular functions have yet been described for these hypothetical proteins, their alteration in response to SCD-1 provides significant information about their putative roles in pathogen defense.
authors.affiliation: Division of Diagnostics and Biochemistry, CSIR-Institute of Genomics and Integrative Biology , University Campus, Mall Road, Delhi-110007, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.forename: Shilpi
authors.initials: S
authors.lastname: Gupta
authors.forename: Bharat
authors.initials: B
authors.lastname: Singh
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gupta
authors.forename: Gainda L
authors.initials: GL
authors.lastname: Sharma
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology*; D005656:Fungal Proteins / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D058990:Molecular Targeted Therapy; D060066:Protein Interaction Maps; D021381:Protein Transport / Q000187:drug effects; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D003374:Coumarins; D005656:Fungal Proteins; C000593034:N,N,N-triethyl-11-(4-methyl-2-oxo-2H-chromen-7-yloxy)-11-oxoundecan-1-aminium; D020543:Proteome; D000644:Quaternary Ammonium Compounds