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.
