title: Dermatophytic defensin with antiinfective potential.
abstract: Fungi are a newly emerging source of peptide antibiotics with therapeutic potential. Here, we report 17 new fungal defensin-like peptide (fDLP) genes and the detailed characterization of a corresponding synthetic fDLP (micasin) from a dermatophyte in terms of its structure, activity and therapeutic potential. NMR analysis showed that synthetic micasin adopts a "hallmark" cysteine-stabilized α-helical and β-sheet fold. It was active on both gram-positive and gram-negative bacteria, and importantly it killed two clinical isolates of methicillin-resistant Staphylococcus aureus and the opportunistic pathogen Pseudomonas aeruginosa at low micromolar concentrations. Micasin killed approximately 100% of treated bacteria within 3 h through a membrane nondisruptive mechanism of action, and showed extremely low hemolysis and high serum stability. Consistent with these functional properties, micasin increases survival in mice infected by the pathogenic bacteria in a peritonitis model. Our work represents a valuable approach to explore novel peptide antibiotics from a large resource of fungal genomes.
authors.affiliation: Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, 100101 Beijing, China. Zhusy@ioz.ac.cn
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Peta J
authors.initials: PJ
authors.lastname: Harvey
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D003883:Arthrodermataceae / Q000235:genetics*; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D023082:Defensins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D000890:Anti-Infective Agents; D018076:DNA, Complementary; D023082:Defensins; D005656:Fungal Proteins; D010455:Peptides; C574456:micasin