Xu Dawei, Chen Weike, Tobin-Miyaji Yuto J, Sturge Carolyn R, Yang Su, Elmore Brendan, Singh Anju, Pybus Christine, Greenberg David E, Sellati Timothy J, Qiang Wei, Dong He
Department of Chemistry and Biomolecular Science , Clarkson University , Potsdam , New York 13699 , United States.
Department of Chemistry and Biochemistry , The University of Texas at Arlington , Arlington , Texas 76019 , United States.
ACS Infect Dis. 2018 Sep 14;4(9):1327-1335. doi: 10.1021/acsinfecdis.8b00069. Epub 2018 Jul 9.
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.
抗菌肽（AMPs）的发现为克服细菌对常用抗生素的耐药性流行带来了巨大的希望和机遇。然而，它们的广泛应用和转化为临床应用受到中度至重度溶血活性和细胞毒性的阻碍。在此，我们展示并验证了一个用于构建具有血液和细胞相容性的基于AMPs的纳米材料的超分子平台，称为自组装抗菌纳米纤维（SAANs）。SAANs是我们抗菌治疗平台的“核心”，是从头设计的AMPs的超分子组装体，它们经过程序化的自组装形成纳米结构纤维，在细菌膜上“打孔”，从而杀死细菌病原体。在这项研究中，我们进行了固态核磁共振光谱分析，结果表明主要是反平行β-折叠组装体而非单体与脂质体相互作用。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微观证据，即自组装纳米纤维与细菌细胞物理接触，导致局部膜变形和破裂。虽然SAANs能有效杀死细菌，但由于其纳米颗粒性质，它们被发现可以无害地穿过哺乳动物细胞膜，膜积累大大减少，并且与天然AMPs相比具有出色的细胞相容性和血液相容性。通过这些系统研究，我们期望建立这种用于SAANs定制设计的新范式，它将提供对杀菌活性和细胞相容性的精确、可调控制，并有可能克服传统AMPs的缺点。
