N-terminal modifications of Polymyxin B nonapeptide and their effect on antibacterial activity.
Polymyxin B (PMB) is a potent antibacterial lipopeptide composed of a positively charged cyclic peptide ring and a fatty acid containing tail. Polymyxin B nonapeptide (PMBN), the deacylated amino derivative of polymyxin B, is much less bactericidal but able to permeabilize the outer membrane of Gram-negative bacteria and to neutralize the toxic effects of lipopolysaccharide (LPS). In this study, we synthesized and evaluated the antibacterial and LPS neutralizing activities of four PMBN analogs modified at their N-terminal. Our results suggest that oligoalanyl substitutions of PMBN do not effect most of PMBN activities. However, a hydrophobic aromatic substitution generated a PMB-like molecule with high antibacterial activity and significant reduced toxicity.
Tsubery
H
H
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Ofek
I
I
Cohen
S
S
Fridkin
M
M
D020816:Amino Acid Motifs; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000502:physiology; D002478:Cells, Cultured / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000093242:Interleukin-6 Inhibitors
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D011112:Polymyxin B; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C038934:polymyxin B nonapeptide