Development of Novel Antimicrobial Peptides

This project for a Postdoctoral Schrödinger Fellowship is designed to synthesize and analyze novel linear antimicrobial peptides. In the face of ever-increasing resistance to existing antimicrobial drugs, an enormous effort is underway to exploit the potential of these peptides and to design new potent antimicrobial peptides which have low mammalian cell toxicity. The studies proposed here represent a strategic and coordinated synthetic and biophysical approach to the design of novel antimicrobial ß-sheet forming peptides. New cystein-free peptide analogs will be generated using combinatorial chemistry. Conformationally defined peptide analogs will be synthesized by varying the hydrophobic and hydrophilic faces of a beta-sheet peptide. The peptide libraries will be synthesized as positional scanning libraries and screened for antimicrobial and hemolytic activities. After having identified peptides with high therapeutic index biophysical studies will be performed to determine the precise mechanisms by which these compounds interact with and kill microorganisms and the underlying basis of selectivity between bacterial and mammalian cells. These studies include the determination of membrane-induced secondary structures and of peptide affinities to various membrane surfaces. The combination of combinatorial chemistry and novel biophysical methods for analyzing peptide-membrane interactions is a powerful approach which will advance the understanding of the molecular basis of these peptides and provides new criteria for the design of more potent and selective therapeutics.