Development of Synthetic Antimicrobial Peptides as Therapeutic Agents to Treat Drug Resistant Bacterial and Fungal Infections

The continued evolution of multiple drug resistant organisms associated with common bacterial and fungal infections have become a critical and life threatening challenge facing modern medicine. To overcome this challenge new therapeutic agents that kill these organisms via novel mechanisms of action must be developed. Antimicrobial peptides offer several advantages as potential therapeutic agents against multiple drug resistant organisms. Their greatest advantage is their unique mechanism of action which involves first the disruption of the target’s cell membrane followed by lysis of the cell thus causing cell death. However, natural antimicrobial peptides also have several inherent disadvantages these included low metabolic stability, lack of bacterial strain selectivity and toxicity toward human cells. In this chapter the development of synthetic antimicrobial peptides containing both natural and unnatural amino acids as well as peptidomimetics designed to address these disadvantages will be discussed. An overview of the physicochemical properties required for antimicrobial activity will be presented with emphasis on the logic of the process of designing new antimicrobial peptides. Specific examples of synthetic antimicrobial peptides will be presented to highlight the application of various approaches to address the issues of metabolic stability, increasing the selectivity for prokaryotic verses eukaryotic cells, as well as increasing bacterial strain selectivity and potency. In addition the chemical analysis methods of Circular Dichroism spectroscopy (CD), isothermal calorimetry (ITC) and fluorescence spectroscopy to monitor calcein induced leakage from liposomes will be discussed. These techniques provide physicochemical information concerning peptide-lipid interactions which provide critical insight for the design of therapeutically useful antimicrobial peptides.

Keywords: Antimicrobial peptides, unnatural amino acids, peptide-lipid interactions, peptidomimetics, β-peptides, organism selectivity, circular dichroism spectroscopy, isothermal calorimetry, mechanism of antibacterial activity.