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About 70 fungal defensin-like peptides (fDLPs) in five new genera were identified.A new synthetic defensin (scedosporisin) was characterized and found active against several clinical resistant bacteria.A local hydrophobic patch of scedosporisin-2 is experimentally identified as associated with the antimicrobial activity.Fungi-derived defensins are a class of antimicrobial peptides with therapeutic potential due to their high antibacterial efficacy and low toxicity. Based on the genomic strategy, we have identified 68 fungal defensin-like peptides (fDLPs) in five new genera, including Trichosporon, Apophysomyces, Lichtheimia, Beauveria and Scedosporium and characterized a new synthetic defensin (scedosporisin) from an invasive fungus. It was active against Gram-positive bacteria but not active against negative bacteria. Importantly, it killed several clinical resistant isolates such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci at low molecular concentrations. Scedosporisin showed low hemolysis and cytotoxicity and high serum stability. The killing kinetics of scedosporisin-2 against a clinical isolate of MRSA showed that it killed the bacteria more rapidly than that of vancomycin. Homology modeling analysis show that scedosporisin adopted a typical cysteine stabilized α-helical and β-sheet fold with a local hydrophobic patch. Scedosporisin significantly improved the survival rate of mice in the peritonitis model. This work has greatly expanded the library of fDLPs, and successfully selected leading molecules for antimicrobial drug reserves.