Repeating a Five-Residue Melittin Fragment Gives Non-Haemolytic β-Sheet Antibacterial Peptides
- Melittin is potently antimicrobial but too haemolytic to be a lead; the authors built 10-, 15- and 20-mer peptides from repeats of its C-terminal WIKRK segment.
- The 15- and 20-mers adopt β-sheet structure in bacterial-mimetic vesicles, with negligible haemolysis and cytotoxicity and strong activity against bacteria and mycobacteria.
- They were active in an E. coli mouse infection model by intravenous dosing and inhibited transcription and translation, suggesting an intracellular mechanism.
💡 Points
Shrinking melittin to a tandem repeat and flipping it from helix to sheet is a neat way to decouple killing from lysis. The intracellular mode of action is the interesting part, since it points away from the membrane-disruption liabilities that kill most AMPs in the clinic. I'd still want protease stability and plasma binding data before believing the in vivo window.