Acyl-substituted dermaseptin S4 derivatives with improved bactericidal properties, including on oral microflora

Antimicrob Agents Chemother. 2006 Dec;50(12):4153-60. doi: 10.1128/AAC.00750-06. Epub 2006 Oct 16.

Abstract

The 15-mer dermaseptin S4 derivative S4(1-15) was recently shown to exhibit potent activity against oral pathogens associated with caries and periodontitis. Here, we investigated possible modes for improving the peptide's properties through systematic replacement of an N-terminal amino acid(s) with various fatty acids that modulate the peptide's hydrophobicity and/or charge. Deletion of 1 to 3 residues led to progressive loss of potency as assessed by MIC experiments performed on four test bacteria. Replacing the deleted amino acids with fatty acids most often resulted in potency recovery or improvement, as evidenced by lower MICs and faster bactericidal kinetics in culture media. Best results were obtained after replacement of the N-terminal dipeptide alanine-leucine with heptanoic (C7) or aminododecanoic (NC12) acid. Circular dichroism analysis correlated antibacterial properties to the peptide's secondary structure. MIC experiments and confocal laser scanning microscopy results indicated that C7-S4(3-15) and NC12-S4(3-15) were bactericidal to various oral pathogens, including those which are immobilized in a biofilm. C7-S4(3-15) performed similarly to or better than (depending on growth medium) IB-367, a peptide assessed in clinical trials for treatment of oral mucositis, reducing CFU counts by >3 log units within 2 min of incubation. Collectively, the data indicate that substitution of fatty acids for amino acids may be a useful strategy in revealing improved derivatives of known antimicrobial peptides and suggest the suitability of such compounds for controlling pathogens associated with oral diseases.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Amphibian Proteins / chemical synthesis
  • Amphibian Proteins / chemistry*
  • Amphibian Proteins / pharmacology*
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemical synthesis
  • Antimicrobial Cationic Peptides / chemistry*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Biofilms / drug effects
  • Circular Dichroism
  • Colony Count, Microbial
  • Fatty Acids / chemistry
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Microbial Sensitivity Tests
  • Microscopy, Confocal
  • Mouth / drug effects*
  • Mouth / microbiology
  • Peptides / pharmacology
  • Protein Structure, Secondary
  • Structure-Activity Relationship

Substances

  • Amphibian Proteins
  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Fatty Acids
  • Peptides
  • dermaseptin
  • antimicrobial peptide IB-367