There is a great need for novel antibiotics, which antimicrobial peptides (AMPs) could potentially satisfy. AMPs are part of the host-defense mechanisms of most multicellular organisms. Certain AMPs directly act on bacterial cell membranes without the need for interaction with target proteins prone to potential mutation. This raises the question of which molecular features equip AMPs with their direct membranolytic antimicrobial activity. We have tried to pin down these features by synthesizing and testing a range of linear cationic peptides with a fixed a-helical amphipathic secondary structure but varying amino acid sequence. Novel peptides were derived from a gradual transformation of the AMPs Aurein2.2d2 (GLFDIVKKVVGALG-NH2) to Klk14 (KLLKLLKKLLKLLK-NH2) and vice versa. Of the 18 synthesized peptides, 11 peptides inhibited the growth of S.aureus at concentrations of below 50µM. Hemolysis and HDME cell selectivity assays revealed that six peptides exhibit therapeutic indices greater than three. Circular dichroism and nuclear magnetic resonance spectroscopy confirmed an overall helical secondary structure of all molecules. Molecular dynamics simulations in membrane mimicking environment additionally supported these findings. In conclusion, the presented rectilinear morphing strategy is a simple method to explore peptide sequence space, while retaining overall structural features. By help of this new approach, we have discovered novel synthetic AMPs that are potent and selective towards Gram-positive bacteria.

Morphing of antimicrobial peptides towards selective antibiotic agents

254th National Meeting (2017)

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