Small AntiMicrobial Peptide With in Vivo Activity Against Sepsis

Molecules. 2019 May 1;24(9):1702. doi: 10.3390/molecules24091702.

Abstract

Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic β-amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice.

Keywords: polycationic β-amino acids; sepsis; small antimicrobial peptides.

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Anti-Infective Agents / administration & dosage*
  • Anti-Infective Agents / chemical synthesis*
  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Antimicrobial Cationic Peptides / administration & dosage*
  • Antimicrobial Cationic Peptides / chemical synthesis*
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / pharmacology
  • Disease Models, Animal
  • Drug Design
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Humans
  • Mice
  • Microbial Sensitivity Tests
  • Molecular Mimicry
  • Proteolysis
  • Sepsis / drug therapy*
  • Sepsis / etiology
  • Sepsis / microbiology

Substances

  • Amino Acids
  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides