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The effect of substituting two glycine residues, Gl[y.sup.8] and Gl[y.sup.13] with Ala or Pro on the peptide's structure and biological activities is examined to develop novel antibiotic peptides with selectivity for bacterial cells. It is demonstrated that the Gly-Pr[o.sup.8] is an excellent candidate lead compound for the development of novel antimicrobial agents.

The role of the leader peptide of McjA is examined and is shown that only the eight C-terminal amino acids of this leader peptide are needed for maturation of the antimicrobial peptide microcin J25 (MccJ25). Alanine scanning mutagenesis studies have shown that the Thr-35 residue in the leader peptide is vital for correct processing of McjA into mature MccJ25, whereas the charged amino acids have not played a major role in the maturation of MccJ25.

The biological activity of the selected peptides from the combinatorial library in bacteria, fungi and mammalian cells is studied to characterize the selected peptides and to compare the activity of antimicrobial peptides (AMPs) in vitro and in vivo. The analysis has shown that the methods focusing on screening peptide libraries in vitro for membranes with the appropriate interfacial activity has enabled the design, selection and discovery of novel, potent and broad-spectrum membrane-active antibiotics.

A detailed characterization of peptide-membrane interactions of dermaseptin (Drs B2), which is a 33-residue-long cationic, [alpha]-helical antimicrobial peptide endowed with membrane-damaging activity against a wide range of microorganisms such as bacteria, yeast, fungi, and protozoa is described. The results showed that Drs B2 could adopt a flexible helix-hinge-helix structure in a membrane environment with a strong positive curvature strain that permits the concomitant insertion of the strongly hydrophobic N- and C-termini of the peptide into the acyl core of the membrane.

The development of a concise route for the preparation of new tetra-orthogonally protected (2S,6R)-lanthionines is described. The new orthogonally protected lanthionines could be used to study the lantibiotic family of antimicrobial peptides.

A method based on selected amino acid alterations in the peptide template was used to identify novel C3a peptide variants with enhanced antimicrobial effects. The results provide insights into the structure-activity relationships associated with the function and specificity of antimicrobial C3a and related analogues and also into the forces that drive evolution of antimicrobial peptides.

A series of guidelines useful for the future design of short cationic antimicrobial peptides with high resilience against tryptic degradation are presented. The guidelines can also be applied to generate stabilization of other small cationic peptides against tryptic degradation.

Polymers based on m-phenylene ethylenes (mPE) were designed and synthesized to mimic the amphiphilic, cationic, and rigid structure of antimicrobial peptides (AMPs) and were found to be good mimics of AMPs in terms of their high potency toward microbes and low hemolytic activities. Two mPEs were found to readily insert into anionic model bacterial membranes but to differ in the degree of selectivity between bacterial and mammalian erythrocyte model membranes, demonstrating that mPEs can mimic AMPs' membrane disordering.