Scientists studied a short piece of the human antimicrobial peptide LL‑37 and found that swapping one amino‑acid for cysteine lets the pieces form disulfide‑linked pairs that stack into stable fibrils, which changes how well they kill bacteria. The work shows that where the cysteine is placed controls activity and that the structures are sensitive to oxidation‑reduction conditions, explaining why nature avoids such designs.

Human LL-37_17-29 is an antimicrobial peptide forming thermostable supramolecular fibrils that surround bacterial cells. The crystal structure of LL-37_17-29 bearing an I24C substitution of most buried position in the fibril revealed disulfide-bonded dimers that further assembled into a fibrillar structure of densely packed helices<i>.</i> We further demonstrated the position-dependent controllable antibacterial activity of LL-37_17-29 I24C and other cysteine mutants, mediated by regulation of intermolecular disulfide bonds and their role in the formation of supramolecular structures. The morphology of the fibrils and their antibacterial mechanism of action might be dependent on their interactions with specific bacteria. The significant effect of disulfide bonds on the assembly into supramolecular structures and their sensitivity to reducing/oxidizing conditions may explain why short helical antimicrobial peptides with a single cysteine and an odd number of cysteines are selected against in nature.