Generation and characterization of the antibacterial activity of a novel hybrid antimicrobial peptide comprising functional domains from different insect cecropins.

The search for new antimicrobial compounds involves finding novel sources of chemotherapeutic compounds or manipulating and combining structures from existing molecules. Small antimicrobial peptides (AMPs) are components of innate immune defenses characterized in greatest detail in insect-derived AMPs. We have generated hybrid AMPs (hAMPs) by combining functional motifs from different insect AMPs as a proof of principle that we can generate molecules with lower minimum inhibitory concentrations, and with different activity and target specificity than either parent molecule. A two-helix, cecropin-like hAMP was created by linking the N-terminal alpha helix of cecropin A from Aedes aegypti to the C-terminal alpha helix of cecropin A1 from Drosophila melanogaster. This molecule exhibits antibacterial activity at sub-micromolar concentrations with a target specificity that differs from either parent molecule. Antibacterial activity of the hybrid molecule was found to be greater against Gram-negative than Gram-positive bacteria. No hemolysis was observed in sheep red blood cells exposed to concentrations up to 50 micromol/L, suggesting the peptide is not detrimental to eukaryotic cells.