Bacterial Phospholipid-Inducible Helix-Transformable Antimicrobial Polypeptides
Xinshuang Zhang, Dong Luo, Rongqing Xia, K. Wu, Xueyi Li, Jingxian Chen, Huosheng Zhou, Jie Hu, Songyin Huang, Shuyi Jia, Chengrun Li, Yan Bao, Houbing Zhang, Liping Zhao, Lu Cai, Menghua Xiong
Abstract
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.