Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria

J Med Chem. 2000 Aug 10;43(16):3085-92. doi: 10.1021/jm0000057.

Abstract

Polymyxin B nonapeptide (PMBN), a cationic cyclic peptide derived by enzymatic processing from the naturally occurring peptide polymyxin B, is able to increase the permeability of the outer membrane of Gram-negative bacteria toward hydrophobic antibiotics probably by binding to the bacterial lipopolysaccharide (LPS). We have synthesized 11 cyclic analogues of PMBN and evaluated their activities compared to that of PMBN. The synthetic peptides were much less potent than PMBN in their capacity to sensitize Escherichia coli and Klebsiella pneumoniae toward novobiocin and to displace dansyl-PMBN from Escherichia coli LPS. Moreover, unlike PMBN, none of the analogues were able to inhibit the growth of Pseudomonas aeruginosa. The structural-functional features of PMBN were characterized and identified with regard to the ring size, the distance between positive charges and peptide backbone, the chirality of the DPhe-Leu domain, and the nature of the charged groups. Apparently, the structure of PMBN is highly specific for efficient perturbation of the outer membrane of Gram-negative bacteria as well as for LPS binding. The present study further increases our understanding of the complex PMBN-LPS and may, potentially, enable the design of compounds having enhanced permeabilization potency of the Gram-negative outer membrane.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Chromatography, High Pressure Liquid
  • Circular Dichroism
  • Drug Design
  • Drug Evaluation, Preclinical
  • Escherichia coli / chemistry
  • Escherichia coli / drug effects
  • Escherichia coli / isolation & purification
  • Gram-Negative Bacteria / drug effects*
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / isolation & purification
  • Lipopolysaccharides / chemistry
  • Microbial Sensitivity Tests
  • Polymyxin B / analogs & derivatives*
  • Polymyxin B / chemical synthesis
  • Polymyxin B / chemistry
  • Polymyxin B / pharmacology
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / isolation & purification
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Lipopolysaccharides
  • polymyxin B nonapeptide
  • Polymyxin B