Peptide Fragments of a β-Defensin Derivative with Potent Bactericidal Activity

Natalie L Reynolds, Martin De Cecco, Karen Taylor, Chloe Stanton, Fiona Kilanowski, Jason Kalapothakis, Emily Seo, Dusan Uhrin, Dominic Campopiano, John Govan, Derek Macmillan, Perdita Barran, Julia R Dorin

Research output: Contribution to journalArticlepeer-review

Abstract

Beta-defensins are known to be both antimicrobial and able to chemoattract various immune cells. Although the sequences of paralogous genes are not highly conserved, the core defensin structure is retained. Defb14-1C(V) has bactericidal activity similar to that of its parent peptide (murine beta-defensin Defb14) despite all but one of the canonical six cysteines being replaced with alanines. The 23-amino-acid N-terminal half of Defb14-1C(V) is a potent antimicrobial while the C-terminal half is not. Here, we use a library of peptide derivatives to demonstrate that the antimicrobial activity can be localized to a particular region. Overlapping fragments of the N-terminal region were tested for their ability to kill Gram-positive and Gram-negative bacteria. We demonstrate that the most N-terminal fragments (amino acids 1 to 10 and 6 to 17) are potent antimicrobials against Gram-negative bacteria whereas fragments based on sequence more C terminal than amino acid 13 have very poor activity against both Gram-positive and -negative types. We further test a series of N-terminal deletion peptides in both their monomeric and dimeric forms. We find that bactericidal activity is lost against both Gram types as the deletion region increases, with the point at which this occurs varying between bacterial strains. The dimeric form of the peptides is more resistant to the peptide deletions, but this is not due just to increased charge. Our results indicate that the primary sequence, together with structure, is essential in the bactericidal action of this beta-defensin derivative peptide and importantly identifies a short fragment from the peptide that is a potent bactericide.
Original languageEnglish
Pages (from-to)1922-1929
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number5
DOIs
Publication statusPublished - May 2010

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