1. Novozymes A/S, 2880 Bagsvaerd, Denmark
2. National Center for Antimicrobials and Infection Control, Statens Serum Institut, 2300 Copenhagen S, Denmark
3. Novo Nordisk A/S, 2880 Bagsvaerd, Denmark
4. Novozymes Inc., Davis, California 95616, USA
5. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
6. Departments of Surgery and Pediatrics, Georgetown University Medical Center, Washington DC 20007, USA
7. †Present address: Novo Nordisk A/S, 2769 Maaloev, Denmark
8. *These authors contributed equally to this work

Correspondence to: Hans-Henrik Kristensen¹ Correspondence and requests for materials should be addressed to H.-H.K. (Email: hahk@novozymes.com). Plectasin DNA sequence has been submitted to EMBL with the accession numbers EMBL:AJ964941 and TREMBL:CAI83768. Plectasin coordinates have been deposited to the Protein Data Bank under accession number 1ZFU, and relevant NMR data will be submitted to the Biological Magnetic Resonance Data Bank.

Abstract

Animals and higher plants express endogenous peptide antibiotics called defensins. These small cysteine-rich peptides are active against bacteria, fungi and viruses. Here we describe plectasin—the first defensin to be isolated from a fungus, the saprophytic ascomycete Pseudoplectania nigrella. Plectasin has primary, secondary and tertiary structures that closely resemble those of defensins found in spiders, scorpions, dragonflies and mussels. Recombinant plectasin was produced at a very high, and commercially viable, yield and purity. In vitro, the recombinant peptide was especially active against Streptococcus pneumoniae, including strains resistant to conventional antibiotics. Plectasin showed extremely low toxicity in mice, and cured them of experimental peritonitis and pneumonia caused by S. pneumoniae as efficaciously as vancomycin and penicillin. These findings identify fungi as a novel source of antimicrobial defensins, and show the therapeutic potential of plectasin. They also suggest that the defensins of insects, molluscs and fungi arose from a common ancestral gene.

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