Bacterial Phospholipid-Inducible Helix-Transformable Antimicrobial Polypeptides

The helical conformation of antimicrobial peptides (AMPs) exerts a dual effect: it enhances bactericidal activity while concurrently increasing cytotoxicity by facilitating penetration into mammalian cells, leading to organelle damage. Herein, we report a bacterial phospholipid-inducible, helix-transformable antimicrobial polypeptide (HT-AMP) for enhancing the antimicrobial selectivity. The HT-AMP, C6-10, which has a charge-to-backbone span of 10 σ-bonds, adopts a moderate intrinsic helicity of 38% due to side-chain charge repulsion. This restrained conformation significantly reduces AMP penetration into mammalian cells, thereby minimizing mitochondrial damage. C6-10 shows a high affinity for the bacterial phospholipid phosphatidylglycerol (PG). Upon PG recognition, the side-chain charge repulsion of C6-10 is reduced, and its helicity increases to ∼77%, exhibiting robust antibacterial activity. Further extending the hydrophobicity of the C-terminal group increases the helicity of polypeptides, leading to enhanced mammalian cellular internalization and mitochondrial damage. C6-10 demonstrated low toxicity toward organs following intravenous administration and exhibited significant antibacterial efficacy in both a bladder infection model and a sepsis model. Overall, this PG-triggered helix-transformable strategy provides an effective approach to improving the antibacterial selectivity of AMPs.