The Acyl Group as the Central Element of the Structural Organization of Antimicrobial Lipopeptide

摘要

Incorporation of non-natural amino acids or non-amino acid groups into peptides, such as β-amino acids, carbohydrates, nucleotides, or fatty acids extends their spectrum of activities as well as the accessible conformational space. In most of the determined structures of such hybrids, the peptide and non-peptide segment are segregated into two separate domains. Here we report on the solution structure of an antimicrobial lipopeptide, which shows that the acyl chain is tightly intertwined with the amino-acid residues. An acyl chain is present on several natural peptide antibiotics produced by nonribosomal synthesis. The acyl chain of polymyxin B, the archetypal lipopolysaccharide (LPS) neutralizing lipopeptide is essential for its antimicrobial activity. Following the paradigm of polymyxin B, conjugation of cationic antimicrobial peptides with fatty acid chains improved their antimicrobial activity against Gram-negative and Gram-positive bacteria but also neutralization of LPS. An ideal antimicrobial agent should display not only antimicrobial activity but also the ability to bind to and neutralize bacterial endotoxin in order to prevent septic (or endotoxic) shock, which accounts for more than 200 000 deaths in the U.S. every year.