Lipid binding and membrane penetration of polymyxin B derivatives studied in a biomimetic vesicle system

Marina Katz, Haim Tsubery, Sofiya Kolusheva, Alex Shames, Mati Fridkin, Raz Jelinek

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Understanding membrane interactions and cell-wall permeation of Gram-negative bacteria is of great importance, owing to increasing bacterial resistance to existing drugs and therapeutic treatments. Here we use biomimetic lipid vesicles to analyse membrane association and penetration by synthetic derivatives of polymyxin B (PMB), a potent naturally occurring antibacterial cyclic peptide. The PMB analogues studied were PMB non-apeptide (PMBN), in which the hydrophobic alkyl residue was cleaved, PMBN diastereomer containing D- instead of L-amino acids within the cyclic ring (dPMBN) and PMBN where the hydrophobic alkyl chain was replaced with an Ala6 repeat (Ala 6-PMBN). Peptide binding measurements, colorimetric transitions induced within the vesicles, fluorescence quenching experiments and ESR spectroscopy were applied to investigate the structural parameters underlying the different membrane-permeation profiles and biological activities of the analogues. The experiments point to the role of negatively charged lipids in membrane binding and confirm the prominence of lipopolisaccharide (LPS) in promoting membrane association and penetration by the peptides. Examination of the lipid interactions of the PMB derivatives shows that the cyclic moiety of PMB is not only implicated in lipid attachment and LPS binding, but also affects penetration into the inner bilayer core. The addition of the Ala 6 peptide moiety, however, does not significantly promote peptide insertion into the hydrophobic lipid environment. The data also indicate that the extent of penetration into the lipid bilayer is not related to the overall affinity of the peptides to the membrane.

Original languageEnglish
Pages (from-to)405-413
Number of pages9
JournalBiochemical Journal
Volume375
Issue number2
DOIs
StatePublished - 15 Oct 2003

Keywords

  • Antibacterial peptides
  • Fluorescence quenching
  • Membranes
  • Polydiacetylene
  • Polymyxin B

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