The discovery of antimicrobial peptides (AMPs) has brought tremendous promise and opportunities to overcome the prevalence of bacterial resistance to commonly used antibiotics. However, their widespread use and translation into clinical application is hampered by the moderate to severe hemolytic activity and cytotoxicity. Here, we presented and validated a supramolecular platform for the construction of hemo- and cytocompatible AMP-based nanomaterials, termed self-assembling antimicrobial nanofibers (SAANs). SAANs, the “nucleus” of our antimicrobial therapeutic platform, are supramolecular assemblies of de novo designed AMPs that undergo programmed self-assembly into nanostructured fibers to “punch holes” in the bacterial membrane, thus killing the bacterial pathogen. In this study, we performed solid-state NMR spectroscopy showing predominant antiparallel β-sheet assemblies rather than monomers to interact with liposomes. We investigated the mode of antimicrobial action of SAANs using transmission electron microscopy and provided compelling microscopic evidence that self-assembled nanofibers were physically in contact with bacterial cells causing local membrane deformation and rupture. While effectively killing bacteria, SAANs, owing to their nanoparticulate nature, were found to cross mammalian cell membranes harmlessly with greatly reduced membrane accumulation and possess exceptional cytocompatibility and hemocompatibility compared to natural AMPs. Through these systematic investigations, we expect to establish this new paradigm for the customized design of SAANs that will provide exquisite, tunable control of both bactericidal activity and cytocompatibility and can potentially overcome the drawbacks of traditional AMPs.

中文翻译：

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细胞相容性自组装抗菌纳米纤维的制备及显微和光谱学表征

抗菌肽（AMPs）的发现为克服细菌对常用抗生素的抗药性带来了广阔的前景和机遇。然而，它们的广泛使用和转化为临床应用受到中度至严重的溶血活性和细胞毒性的阻碍。在这里，我们介绍并验证了一种用于构建血液和细胞相容性AMP基纳米材料的超分子平台，该平台称为自组装抗微生物纳米纤维（SAAN）。SAAN是我们抗菌治疗平台的“核心”，是从头开始的超分子组装体设计的AMP经过程序化的自组装成纳米结构的纤维，以在细菌膜上“打孔”，从而杀死细菌病原体。在这项研究中，我们进行了固态NMR光谱分析，显示了主要的反平行β-sheet组件，而不是与脂质体相互作用的单体。我们使用透射电子显微镜研究了SAANs的抗菌作用模式，并提供了令人信服的显微镜证据，表明自组装的纳米纤维与细菌细胞物理接触，引起局部膜变形和破裂。SAANs虽然可以有效杀死细菌，但由于其纳米颗粒的性质，可以无害地穿越哺乳动物细胞膜，大大减少了膜的积聚，并且与天然AMP相比具有优异的细胞相容性和血液相容性。