title: Copsin, a novel peptide-based fungal antibiotic interfering with the peptidoglycan synthesis.
abstract: Fungi and bacteria compete with an arsenal of secreted molecules for their ecological niche. This repertoire represents a rich and inexhaustible source for antibiotics and fungicides. Antimicrobial peptides are an emerging class of fungal defense molecules that are promising candidates for pharmaceutical applications. Based on a co-cultivation system, we studied the interaction of the coprophilous basidiomycete Coprinopsis cinerea with different bacterial species and identified a novel defensin, copsin. The polypeptide was recombinantly produced in Pichia pastoris, and the three-dimensional structure was solved by NMR. The cysteine stabilized α/β-fold with a unique disulfide connectivity, and an N-terminal pyroglutamate rendered copsin extremely stable against high temperatures and protease digestion. Copsin was bactericidal against a diversity of Gram-positive bacteria, including human pathogens such as Enterococcus faecium and Listeria monocytogenes. Characterization of the antibacterial activity revealed that copsin bound specifically to the peptidoglycan precursor lipid II and therefore interfered with the cell wall biosynthesis. In particular, and unlike lantibiotics and other defensins, the third position of the lipid II pentapeptide is essential for effective copsin binding. The unique structural properties of copsin make it a possible scaffold for new antibiotics.
authors.affiliation: From the Institute of Microbiology and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Essig
authors.affiliation: the Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hofmann
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology, Pharmaceutical Microbiology Section, University of Bonn, Bonn 53115, Germany, and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Münch
authors.affiliation: From the Institute of Microbiology and.
authors.forename: Savitha
authors.initials: S
authors.lastname: Gayathri
authors.affiliation: From the Institute of Microbiology and.
authors.forename: Markus
authors.initials: M
authors.lastname: Künzler
authors.affiliation: From the Institute of Microbiology and.
authors.forename: Pauli T
authors.initials: PT
authors.lastname: Kallio
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology, Pharmaceutical Microbiology Section, University of Bonn, Bonn 53115, Germany, and.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.affiliation: the Institute of Molecular Biology and Biophysics, Swiss Federal Institute of Technology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wider
authors.affiliation: the Institute of Medical Microbiology, Immunology, and Parasitology, Pharmaceutical Microbiology Section, University of Bonn, Bonn 53115, Germany, and the German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung), partner site Bonn-Cologne, Bonn 53115, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schneider
authors.affiliation: From the Institute of Microbiology and markus.aebi@micro.biol.ethz.ch.
authors.forename: Markus
authors.initials: M
authors.lastname: Aebi
mesh_terms: D000363:Agaricales / Q000254:growth & development / Q000378:metabolism*; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D018920:Coculture Techniques; D023082:Defensins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010457:Peptidoglycan / Q000096:biosynthesis*; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D023082:Defensins; D005656:Fungal Proteins; D010457:Peptidoglycan; C000623033:copsin protein, Coprinopsis cinerea
keywords: Antibiotic Resistance; Antibiotics; Antimicrobial Peptide (AMP); Bacterial-Fungal Interaction (BFI); Fungal Secretome; Fungi; Lipid II