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Antimicrobial Agents and Chemotherapy, September 2003, p. 2804-2809, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2804-2809.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antimicrobial Characterization of Human ß-Defensin 3 Derivatives

David M. Hoover,1 Zhibin Wu,2 Kenneth Tucker,3 Wuyuan Lu,2 and Jacek Lubkowski1*

Macromolecular Crystallography Laboratory,1 Opportunistic Infection Laboratory, DCTD/DTP, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Frederick, Maryland 21702,3 Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland 212012

Received 15 November 2002/ Returned for modification 2 April 2003/ Accepted 12 June 2003

Human ß-defensin 3 (hBD3) is a highly basic 45-amino-acid protein that acts both as an antimicrobial agent and as a chemoattractant molecule. Although the nature of its antimicrobial activity is largely electrostatic, the importance of the molecular structure on this activity is poorly understood. Two isoforms of hBD3 were synthesized: the first with native disulfide linkages and the second with nonnative linkages. In a third synthetic peptide, all cysteine residues were replaced with {alpha}-aminobutyric acid, creating a completely linear peptide. A series of six small, linear peptides corresponding to regions of hBD3 with net charges ranging from +4 to +8 (at pH 7) and lengths ranging from 9 to 20 amino acids were also synthesized. The linear full-length peptide showed the highest microbicidal activity against Escherichia coli and Staphylococcus aureus, while all three full-length forms showed equal activity against Candida albicans. The linear peptide also showed high activity against Enterococcus faecium and Pseudomonas aeruginosa. Peptides corresponding to the C terminus showed higher activities when tested against E. coli, with the most active peptides being the most basic. However, only the peptide corresponding to the N terminus of hBD3 showed any activity against S. aureus and C. albicans. Further, N-terminal deletion mutants of native hBD3 showed diminished activities against S. aureus. Thus, the antimicrobial properties of hBD3 derivatives are determined by both charge and structure.

* Corresponding author. Mailing address: Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702. Phone: (301) 846-5494. Fax: (301) 846-7101. E-mail: jacek{at}ncifcrf.gov.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2804-2809, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2804-2809.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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