RAPID IDENTIFICATION OF COMPOUNDS WITH ENHANCED ANTIMICROBIAL ACTIVITY BY USING CONFORMATIONALLY DEFINED COMBINATORIAL LIBRARIES

We have combined the strength of our synthetic combinatorial library a pproach for the rapid identification of highly active compounds with p rior knowledge of the relationship between the antimicrobial activitie s of individual peptides with specific induced conformations in order to identify new peptides with enhanced activity relative to a starting known antimicrobial sequence. In the current study, conformationally defined combinatorial libraries were generated based on an 18-mer anti microbial peptide known to be induced into an a-helical conformation i n a lipidic environment. Not only were novel sequences readily identif ied with 10-fold increases in activity, but detailed information about the structure-activity relationships of the peptides studied was also obtained during the deconvolution process. By using circular dichrois m spectroscopy it was found that the individual 18-mer peptides could be induced into alpha-helical conformations on interaction with the ce ll lipid layer and/or sialic acids, which could result in bacterial ce ll lysis due to perturbation of the lipid packing of the cell wall.