Influence of lipidation on the mode of action of a small RW-rich antimicrobial peptide

Biochim Biophys Acta. 2016 May;1858(5):1004-11. doi: 10.1016/j.bbamem.2015.11.009. Epub 2015 Nov 18.

Abstract

Antimicrobial peptides are a potent class of antibiotics. In the Gram-positive model organism Bacillus subtilis the synthetic peptide RWRWRW-NH2 integrates into the bacterial membrane and delocalizes essential peripheral membrane proteins involved in cell wall biosynthesis and respiration. A lysine residue has been added to the hexapeptide core structure, either C or N-terminally. Lipidation of the lysine residues by a C8-acyl chain significantly improved antibacterial activity against both Gram-positive and Gram-negative bacteria. Here, we report a comparative proteomic study in B. subtilis on the mechanism of action of the lipidated and non-lipidated peptides. All derivatives depolarized the bacterial membrane without forming pores and all affected cell wall integrity. Proteomic profiling of the bacterial stress responses to the small RW-rich antimicrobial peptides was reflective of non-disruptive membrane integration. Overall, our results indicate that antimicrobial peptides can be derivatized with lipid chains enhancing antibacterial activity without significantly altering the mechanism of action. This article is part of a Special Issue entitled: Antimicrobial peptides edited by Karl Lohner and Kai Hilpert.

Keywords: Acylation; Antibacterial peptides; Antibiotics; Bacterial membranes; Bacterial stress response; Proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / chemical synthesis
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology*
  • Arginine / chemistry
  • Arginine / metabolism
  • Bacillus subtilis / chemistry
  • Bacillus subtilis / drug effects*
  • Bacillus subtilis / genetics
  • Bacillus subtilis / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Cell Wall / chemistry
  • Cell Wall / drug effects*
  • Cell Wall / metabolism
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Escherichia coli / chemistry
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial*
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Structure-Activity Relationship
  • Tryptophan / chemistry
  • Tryptophan / metabolism

Substances

  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • Tryptophan
  • Arginine