D-enantiomeric Peptides That Eradicate Wild-Type and Multidrug-Resistant Biofilms and Protect Against Lethal Pseudomonas Aeruginosa Infections

Chem Biol. 2015 Feb 19;22(2):196-205. doi: 10.1016/j.chembiol.2015.01.002.

Abstract

In many infections, bacteria form surface-associated communities known as biofilms that are substantially more resistant to antibiotics than their planktonic counterparts. Based on the design features of active antibiofilm peptides, we made a series of related 12-amino acid L-, D- and retro-inverso derivatives. Specific D-enantiomeric peptides were the most potent at inhibiting biofilm development and eradicating preformed biofilms of seven species of wild-type and multiply antibiotic-resistant Gram-negative pathogens. Moreover, these peptides showed strong synergy with conventional antibiotics, reducing the antibiotic concentrations required for complete biofilm inhibition by up to 64-fold. As shown previously for 1018, these D-amino acid peptides targeted the intracellular stringent response signal (p)ppGpp. The most potent peptides DJK-5 and DJK-6 protected invertebrates from lethal Pseudomonas aeruginosa infections and were considerably more active than a previously described L-amino acid peptide 1018. Thus, the protease-resistant peptides produced here were more effective both in vitro and in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Infective Agents / chemistry*
  • Anti-Infective Agents / pharmacology
  • Anti-Infective Agents / therapeutic use
  • Biofilms / drug effects
  • Caenorhabditis elegans / drug effects
  • Drug Resistance, Bacterial / drug effects
  • Microbial Sensitivity Tests
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Peptides / chemistry*
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Pseudomonas Infections / prevention & control
  • Pseudomonas Infections / veterinary
  • Pseudomonas aeruginosa / physiology*
  • Stereoisomerism

Substances

  • Anti-Infective Agents
  • DJK-5 peptide
  • DJK-6 peptide
  • Oligopeptides
  • Peptides