Identifying Novel Antimicrobial Peptides with Therapeutic Potential Against Multidrug-Resistant Bacteria by Using the SPOT Synthesis

Developing of new lead structures against multidrug-resistant bacteria is an urgent need and cationic antimicrobial peptides (AMPs) have the potential to become such a lead structure. Here we provide an overview of a method to screen peptides for antimicrobial activity based on the SPOT synthesis. Three different strategies to study and optimize antimicrobial activity of peptides have been reported, substitution analysis of known AMPs, scrambling of known AMPs, and screening peptide libraries for novel AMP sequences. This screening method has great potential for discovery and optimization of novel antibiotics; many different peptides with low cytotoxicity and superior activity against different pathogenic bacteria have already been discovered and selected candidates were successfully tested in a mouse infection model using Staphylococcus aureus. The combination of this screening method together with quantitative structure-activity relationship (QSAR) approach led to superior active peptide against several clinical isolates of different multidrugresistant bacteria. A variant of this screening method can also be used to discover peptides that are antimicrobial when attached to surfaces, a potentially important application for prevention of implant-associated infection.