TY - JOUR
T1 - Modulation of the hydrophobic domain of polymyxin B nonapeptide
T2 - Effect on outer-membrane permeabilization and lipopolysaccharide neutralization
AU - Tsubery, Haim
AU - Ofek, Itzhak
AU - Cohen, Sofia
AU - Eisenstein, Miriam
AU - Fridkin, Mati
PY - 2002/11/1
Y1 - 2002/11/1
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=0036840627&partnerID=8YFLogxK
U2 - 10.1124/mol.62.5.1036
DO - 10.1124/mol.62.5.1036
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AN - SCOPUS:0036840627
SN - 0026-895X
VL - 62
SP - 1036
EP - 1042
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -