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<p>Drug-resistant bacterial infections increasingly evade available antimicrobials, and many existing antimicrobial peptides remain limited by instability, toxicity to mammalian membranes and high manufacturing cost. Here we introduce a modular peptide technology that self-assembles into nanofibres on bacterial surfaces through a membrane-anchoring biphenyl group, a diphenylalanine linker and a cationic minimalistic peptide that together enable selective disruption of drug-resistant pathogens. Using cryogenic electron microscopy, molecular dynamics simulations, lipid-nanoparticle membrane mimetics and binding thermodynamics, we show that the peptide first forms short nanofibres that dock onto phosphatidylglycerol and then elongates into nanofibres that penetrate and destabilize the bacterial membrane without inducing resistance. The nanofibres retain antibacterial activity when recycled from killed bacteria and outperform vancomycin and several classical antimicrobial peptides against dense bacterial populations in vitro. In a mouse model of methicillin-resistant <i>Staphylococcus aureus</i> pneumonia, inhaled peptide nanofibres eradicate pulmonary infection and restore lung architecture without detectable toxicity. This modular strategy enables the design of potent, selective and low-cost antimicrobials.</p>

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Modular peptide nanofibres that self-assemble on bacterial membranes overcome antimicrobial resistance

  • 期刊论文

  • 发表日期：

    2026年5月20日

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  • Ziao Zhou,
  • Dinghao Chen,
  • Jiang Ouyang,
  • Nan Kong,
  • Hongyue Zhang,
  • Laicheng Zhou,
  • Jing Wang,
  • Tengyan Xu,
  • Wei Chen,
  • Na Kong,
  • Wei Tao,
  • Huaimin Wang

摘要

Drug-resistant bacterial infections increasingly evade available antimicrobials, and many existing antimicrobial peptides remain limited by instability, toxicity to mammalian membranes and high manufacturing cost. Here we introduce a modular peptide technology that self-assembles into nanofibres on bacterial surfaces through a membrane-anchoring biphenyl group, a diphenylalanine linker and a cationic minimalistic peptide that together enable selective disruption of drug-resistant pathogens. Using cryogenic electron microscopy, molecular dynamics simulations, lipid-nanoparticle membrane mimetics and binding thermodynamics, we show that the peptide first forms short nanofibres that dock onto phosphatidylglycerol and then elongates into nanofibres that penetrate and destabilize the bacterial membrane without inducing resistance. The nanofibres retain antibacterial activity when recycled from killed bacteria and outperform vancomycin and several classical antimicrobial peptides against dense bacterial populations in vitro. In a mouse model of methicillin-resistant Staphylococcus aureus pneumonia, inhaled peptide nanofibres eradicate pulmonary infection and restore lung architecture without detectable toxicity. This modular strategy enables the design of potent, selective and low-cost antimicrobials.