From "carpet" mechanism to de-novo designed diastereomeric cell-selective antimicrobial peptides

Living organisms of all types produce a large repertoire of gene-encoded, n et positively charged, antimicrobial peptides as part of their innate immun ity to microbial invasion. Despite significant variations in composition, l ength and secondary structure most antimicrobial peptides are active in mic romolar concentrations, suggesting a common general mechanism for their mod e of action. Man antimicrobial peptides bind bacterial phospholipid membran es up to a threshold concentration, followed by membrane permeation/disinte gration (the "carpet" mechanism). Recent data suggest that the details of t he permeation pathways may vary for different peptides and are assigned to different modes of action. Accumulating, data reveal that the molecular bas is for cell selectivity is the ability of peptides to specifically bind the negatively charged bacterial membrane, as well as their oligomeric state i n solution and in the membrane. Based on the "carpet" mechanism and the rol e of the peptide oligomeric state, a novel group of diastereomeric (contain ing D- and L-amino acids) antimicrobial peptides were developed. These pept ides may serve as promising templates for the future designs of antimicrobi al peptides. (C) 2001 Elsevier Science Inc. All rights reserved.