Antimicrobial Characterization of Human β-Defensin 3 Derivatives

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Abstract
Human β-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 α-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 againstEscherichia coliandStaphylococcus aureus, while all three full-length forms showed equal activity againstCandida albicans. The linear peptide also showed high activity againstEnterococcus faeciumandPseudomonas aeruginosa.Peptides corresponding to the C terminus showed higher activities when tested againstE. coli, with the most active peptides being the most basic. However, only the peptide corresponding to the N terminus of hBD3 showed any activity againstS. aureusandC. albicans. Further, N-terminal deletion mutants of native hBD3 showed diminished activities againstS. aureus. Thus, the antimicrobial properties of hBD3 derivatives are determined by both charge and structure.