Effect of hydrophobic modifications in antimicrobial peptides

• Close correlation between peptide binding to lipid membranes and membrane rupture
• AMP binding is affected by peptide length, charge, hydrophobicity, and secondary structure.
• Hydrophobic end-tagging is efficient for increasing potency also in serum and against multi-resistant strains.
• Toxicity of acyl-modified peptides has restricted their use.
• Through W/F-tagging potent broad spectrum effects can be combined with low toxicity.

With increasing resistance development against conventional antibiotics, there is an urgent need to identify novel approaches for infection treatment. Antimicrobial peptides may offer opportunities in this context, hence there has been considerable interest in identification and optimization of such peptides during the last decade in particular, with the long-term aim of developing these to potent and safe therapeutics. In the present overview, focus is placed on hydrophobic modifications of antimicrobial peptides, and how these may provide opportunities to combat also more demanding pathogens, including multi-resistant strains, yet not provoking unacceptable toxic responses. In doing so, physicochemical factors affecting peptide interactions with bacterial and eukaryotic cell membranes are discussed. Throughout, an attempt is made to illustrate how physicochemical studies on model lipid membranes can be correlated to result from bacterial and cell assays, and knowledge from this translated into therapeutic considerations.

Tryptophan end-tags ⇒ membrane selectivity ⇒ efficient bacterial killing with low eukaryotic cell toxicityFigure optionsDownload as PowerPoint slide