Modulation of the hydrophobic domain of polymyxin B nonapeptide: effect on outer-membrane permeabilization and lipopolysaccharide neutralization.
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.
Tsubery
Haim
H
Department of Organic Chemistry, the Weizmann Institute of Science, Rehovot, Israel.
Ofek
Itzhak
I
Cohen
Sofia
S
Eisenstein
Miriam
M
Fridkin
Mati
M
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002942:Circular Dichroism; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008958:Models, Molecular; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011550:Pseudomonas aeruginosa / Q000187:drug effects
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; C038934:polymyxin B nonapeptide; D011112:Polymyxin B