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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Anti-Infective Agents / pharmacology
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Arthrodermataceae / genetics*
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Base Sequence
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Cloning, Molecular
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DNA, Complementary / chemistry
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DNA, Complementary / genetics
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Defensins / chemistry
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Defensins / genetics*
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Defensins / pharmacology
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Dose-Response Relationship, Drug
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Fungal Proteins / chemistry
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Fungal Proteins / genetics*
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Fungal Proteins / pharmacology
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Hemolysis / drug effects
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Methicillin-Resistant Staphylococcus aureus / drug effects
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Methicillin-Resistant Staphylococcus aureus / growth & development
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Mice
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Mice, Inbred ICR
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Models, Molecular
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Molecular Sequence Data
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Peptides / chemistry
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Peptides / genetics
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Peptides / pharmacology
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Peritonitis / drug therapy
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Peritonitis / microbiology
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Protein Conformation
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Protein Structure, Secondary
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Pseudomonas aeruginosa / drug effects
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Pseudomonas aeruginosa / growth & development
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Sequence Analysis, DNA
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Sequence Homology, Amino Acid
Substances
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Anti-Infective Agents
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DNA, Complementary
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Defensins
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Fungal Proteins
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Peptides
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micasin
Associated data
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GENBANK/JN014007
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GENBANK/JN014008