PT  - JOURNAL ARTICLE
AU  - Haim Tsubery
AU  - Itzhak Ofek
AU  - Sofia Cohen
AU  - Miriam Eisenstein
AU  - Mati Fridkin
TI  - Modulation of the Hydrophobic Domain of Polymyxin B Nonapeptide: Effect on Outer-Membrane Permeabilization and Lipopolysaccharide Neutralization
AID  - 10.1124/mol.62.5.1036
DP  - 2002 Nov 01
TA  - Molecular Pharmacology
PG  - 1036--1042
VI  - 62
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/62/5/1036.short
4100  - http://molpharm.aspetjournals.org/content/62/5/1036.full
SO  - Mol Pharmacol2002 Nov 01; 62
AB  - 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 replacingd-Phe5 with either with d-Trp ord-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.