Modulation of the hydrophobic domain of polymyxin B nonapeptide: effect on outer-membrane permeabilization and lipopolysaccharide neutralization

Mol Pharmacol. 2002 Nov;62(5):1036-42. doi: 10.1124/mol.62.5.1036.


Polymyxin B nonapeptide (PMBN), a cationic cyclic peptide derived from the antibacterial peptide polymyxin B, is capable of specifically increasing the permeability of the outer membrane (OM) of Gram-negative bacteria toward hydrophobic antibiotics. In this study, we evaluated the contribution of the hydrophobic segment of PMBN (i.e., D-Phe(5)-Leu(6)) to this activity. Accordingly, we synthesized four analogs of PMBN by replacing D-Phe(5) with either with D-Trp or D-Tyr and Leu(6) with Phe or Ala and evaluated their ability to bind cell-free lipopolysaccharide (LPS) and increase bacterial OM permeability. Compared with PMBN, [D-Tyr(5)]PMBN and [Ala(6)]PMBN possessed reduced LPS affinity (IC(50) = 2.5, 25, and 12 microM, respectively) and significantly reduced OM permeability and LPS neutralization activity. [Phe(6)]PMBN exhibited rather similar affinity to cell-free LPS (IC(50) = 5 microM) and the same OM permeability capacity as PMBN. However, [D-Trp(5)]PMBN, despite its similar affinity to cell-free LPS (IC(50) = 4 microM), had moderately reduced OM permeability capacity. These results demonstrate the significant role of the PMBN hydrophobic segment in promoting biological activity.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Cell Membrane Permeability / drug effects*
  • Circular Dichroism
  • Drug Interactions
  • Escherichia coli / drug effects
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Lipopolysaccharides / pharmacology*
  • Models, Molecular
  • Polymyxin B / analogs & derivatives*
  • Polymyxin B / chemical synthesis
  • Polymyxin B / chemistry
  • Polymyxin B / pharmacology*
  • Protein Structure, Tertiary
  • Pseudomonas aeruginosa / drug effects


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