Synthesis and biological evaluation of backbone-aminated analogues of gramicidin S

Bioorg Med Chem Lett. 2020 Aug 1;30(15):127283. doi: 10.1016/j.bmcl.2020.127283. Epub 2020 May 22.

Abstract

We report the parallel synthesis of gramicidin S derivatives featuring backbone N-amino substituents. Analogues were prepared by incorporation of N-amino dipeptide subunits on solid support. Nine backbone-aminated macrocycles were evaluated for growth inhibitory activity against ESKAPE pathogens and hemolytic activity against human red blood cells. Diamination of the Orn residues in the β-strand region of gramicidin S was found to enhance broad-spectrum antimicrobial activity without a corresponding increase in hemolytic activity.

Keywords: Amino acid; Antibiotic; Beta-sheet; Peptide; Peptidomimetic.

Publication types

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

MeSH terms

  • Acinetobacter baumannii / drug effects
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enterobacter cloacae / drug effects
  • Enterococcus faecium / drug effects
  • Erythrocytes / drug effects*
  • Gramicidin / chemical synthesis
  • Gramicidin / chemistry
  • Gramicidin / pharmacology*
  • Humans
  • Klebsiella pneumoniae / drug effects
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Pseudomonas aeruginosa / drug effects
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Gramicidin