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

Haim Tsubery, Itzhak Ofek, Sofia Cohen, Miriam Eisenstein, Mati Fridkin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

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-Phe5-Leu6) to this activity. Accordingly, we synthesized four analogs of PMBN by replacing D-Phe5 with either with D-Trp or D-Tyr and Leu6 with Phe or Ala and evaluated their ability to bind cell-free lipopolysaccharide (LPS) and increase bacterial OM permeability. Compared with PMBN, [D-Tyr5]PMBN and [Ala6]PMBN possessed reduced LPS affinity (IC50 = 2.5, 25, and 12 μM, respectively) and significantly reduced OM permeability and LPS neutralization activity. [Phe6]PMBN exhibited rather similar affinity to cell-free LPS (IC50 = 5 μM) and the same OM permeability capacity as PMBN. However, [D-Trp5]PMBN, despite its similar affinity to cell-free LPS (IC50 = 4 μM), had moderately reduced OM permeability capacity. These results demonstrate the significant role of the PMBN hydrophobic segment in promoting biological activity.

Original languageEnglish
Pages (from-to)1036-1042
Number of pages7
JournalMolecular Pharmacology
Volume62
Issue number5
DOIs
StatePublished - 1 Nov 2002

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