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Abstract
Microbial resistance against clinical used antibiotics is on the rise. Accordingly, there is a high demand for new innovative antimicrobial strategies. The host-defense peptide human beta-defensin 1 (hBD-1) is produced continuously by epithelial cells and exhibits compelling antimicrobial activity after reduction of its disulphide bridges. Here we report that proteolysis of reduced hBD-1 by gastrointestinal proteases as well as human duodenal secretions produces an eight-amino acid carboxy-terminal fragment. The generated octapeptide retains antibiotic activity, yet with distinct characteristics differing from the full-length peptide. We modified the octapeptide by stabilizing its termini and by using non-natural D-amino acids. The native and modified peptide variants showed antibiotic activity against pathogenic as well as antibiotic-resistant microorganisms, including E. coli, P. aeruginosa and C. albicans. Moreover, in an in vitro C. albicans infection model the tested peptides demonstrated effective amelioration of C. albicans infection without showing cytotoxity on human cells. In summary, protease degradation of hBD-1 provides a yet unknown mechanism to broaden antimicrobial host defense, which could be used to develop defensin-derived therapeutic applications.
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1 University Hospital Tuebingen, Department of Internal Medicine 1, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249)
2 Stuttgart and University of Tuebingen, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Tuebingen, Germany (GRID:grid.502798.1) (ISNI:0000 0004 0561 903X); University of Gothenburg, Wallenberg Laboratory, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582)
3 University Hospital Tuebingen, Institute of Dermatology, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249); Vetsuisse Faculty, University of Zürich, Institute of Immunology, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650)
4 University Hospital Tuebingen, Institute of Dermatology, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249); University Hospital Tuebingen, Institute of Medical Microbiology and Hygiene, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249)
5 University Hospital Tuebingen, Institute of Dermatology, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249)
6 Stuttgart and University of Tuebingen, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Tuebingen, Germany (GRID:grid.502798.1) (ISNI:0000 0004 0561 903X)
7 University Hospital Tuebingen, Institute of Medical Microbiology and Hygiene, Tuebingen, Germany (GRID:grid.411544.1) (ISNI:0000 0001 0196 8249)
8 University of Zürich, Institute of Immunology, Vetsuisse Faculty, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650)