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Antimicrobial Agents and Chemotherapy, December 2004, p. 4673-4679, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4673-4679.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus-Derived Proteinases

Department of Microbiology, Faculty of Biotechnology,¹ Faculty of Chemistry and Regional Laboratory, Jagiellonian University, Kraków, Poland,² Moyne Institute for Preventive Medicine, Trinity College, Dublin, Ireland,⁶ Microchemical Facility of the Winship Cancer Institute,³ Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta,⁴ Laboratories of Microbial Pathogenesis, Veterans Affairs Medical Center, Decatur,⁵ Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia⁷

Received 2 April 2004/ Returned for modification 26 July 2004/ Accepted 16 August 2004

Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus, a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.

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