Primary amine-functionalized radially amphiphilic polypeptides target bacterial phospholipids in polyanionic matrices for biofilm therapy.

Authors

Yuhao Zhang, Yu Huang, Yeqing He, Xinshuang Zhang, Qianyu Ma, Jiawen Chen, Chanjuan Su, Huosheng Zhou, Songyin Huang, Houbing Zhang, Dong Luo, Yan Bao, Yuqin Shen, Shiyan Xiao, Menghua Xiong

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 34. Pages e2616934123. Aug 25, 2026. Epub Aug 20, 2026.

Abstract

Bacterial biofilm infections, a key contributor to antibiotic resistance, pose a critical global health challenge. Although antimicrobial peptides are promising candidates, their cationic amphipathic structures often lead to nonspecific sequestration by polyanionic biofilm matrix components. Here, we report a class of primary amine-functionalized radially amphiphilic antimicrobial polypeptides (paRAPs) that achieve potent antibiofilm activity by selectively targeting bacterial phosphatidylglycerol (PG) in polyanionic biofilm matrices. Simulation studies support a mechanism of PG-responsive structural rearrangement in paRAPs. In contrast to the compact form of quaternary amine analogs, paRAPs adopt an extended conformation, with outward-facing cationic amine termini that shield the hydrophobic core and thereby reduce nonspecific protein binding. Upon encountering bacterial membranes, strong PG recognition triggers a side-chain rearrangement, reorienting the cationic groups toward the membrane surface and exposing hydrophobic motifs for progressive bilayer insertion and disruption. Supportingly, lengthening the exposed terminal hydrophobic group increased interactions with proteins and mammalian lipids, reduced PG selectivity, and compromised antibiofilm efficacy, underscoring the importance of hidden hydrophobic domains for biofilm bacteria targeting. paRAP showed potent antibiofilm efficacy in vitro and in murine models of both periodontitis and urinary tract infections. Our study provides a PG-targeting strategy for designing matrix-resistant antibiofilm polypeptides.

PMID:
42623443
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.

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