N-terminal modifications of Polymyxin B nonapeptide and their effect on antibacterial activity

Polymyxin B (PMB) is a potent antibacterial lipopeptide composed of a posit ively charged cyclic peptide ring and a fatty acid containing tail. Polymyx in 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 lipopolysaccharid e (LPS). In this study, we synthesized and evaluated the antibacterial and LPS neutralizing activities of four PMBN analogs modified at their N-termin al. Our results suggest that oligoalanyl substitutions of PMBN do not effec t most of PMBN activities. However, a hydrophobic aromatic substitution gen erated a PMB-like molecule with high antibacterial activity and significant reduced toxicity. (C) 2001 Elsevier Science Inc. All rights reserved.