Design, synthesis, and antibacterial evaluation of vancomycin-LPS binding peptide conjugates

Bioorg Med Chem Lett. 2021 Aug 1:45:128122. doi: 10.1016/j.bmcl.2021.128122. Epub 2021 May 17.

Abstract

Developing novel antibiotics is urgently needed with emergency of drug resistance. Vancomycin, the last resort for intractable Gram-positive bacterial infections, is ineffective against Gram-negative bacteria and vancomycin resistant bacteria. Herein, we report a series of novel vancomycin derivatives carrying LPS binding peptides, vancomycin-LPS binding peptide conjugates (VPCs). The LPS binding peptides were conjugated onto 4 sites of vancomycin via CuAAC or maleimide- sulfydryl addition, and the formed VPCs were screened against VISA/VRE and Gram-negative strains. VPCs exhibited enhanced activity against vancomycin resistant bacteria and obtained the activity against Gram-negative bacteria in vitro, providing a novel strategy for vancomycin modification and glycopeptide antibiotics synthesis.

Keywords: Antibacterial activity; LPS binding peptides; Vancomycin analogues; Vancomycin-Peptide Conjugates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Gram-Negative Bacteria / drug effects*
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / pharmacology*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Structure-Activity Relationship
  • Vancomycin / chemistry
  • Vancomycin / pharmacology*

Substances

  • Anti-Bacterial Agents
  • Lipopolysaccharides
  • Peptides
  • Vancomycin