Dendrimer-Based Multivalent Vancomycin Nanoplatform for Targeting the Drug-Resistant Bacterial Surface
Dendrimer-Based Multivalent Vancomycin Nanoplatform for Targeting the Drug-Resistant Bacterial Surface
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DOI：
10.1021/nn3038995
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发表时间：
2013-01-01
期刊：
影响因子：
17.1
通讯作者：
Baker, James R., Jr.
中科院分区：
文献类型：
--
作者：
Choi, Seok Ki;Myc, Andrzej;Baker, James R., Jr.
万古霉素是细菌靶向纳米系统的首选配体。然而，由于其与重编程细胞壁结构的亲和力较差，因此对于新出现的万古霉素耐药物种效率较低。这项研究表明，使用多价策略是克服细菌靶向亲和力限制的有效方法。我们设计了一系列第五代 (G5) 聚酰胺胺 (PAMAM) 树枝状聚合物，在 C 末端以不同价态连接有万古霉素。我们进行了表面等离子共振 (SPR) 研究，以确定它们与两种细胞壁模型的结合亲合力，每种细胞壁模型均由万古霉素敏感 (D)-Ala-(D)-Ala 或万古霉素抗性 (D)-Ala-(D)-Lac 细胞壁前体制成。这些缀合物在测试的细胞壁模型中显示出亲和力显着增强，包括万古霉素抗性模型，其亲和力比游离万古霉素增加了四到五个数量级。通过共聚焦荧光显微镜成像，缀合物对模型表面的紧密吸附与其体外结合万古霉素敏感金黄色葡萄球菌细胞的能力相对应。然后使用该万古霉素平台通过用树枝状聚合物缀合物涂覆氧化铁纳米颗粒来制造氧化铁纳米颗粒的表面，并且所得到的树枝状聚合物覆盖的磁性纳米颗粒被证明能够快速隔离细菌细胞。总之，本文研究了基于树枝状大分子的万古霉素缀合物与细菌细胞壁紧密、多价结合的生物物理基础，并提出了该纳米平台在靶向革兰氏阳性细菌方面的潜在新用途。
Vancomycin represents the preferred ligand for bacteria-targeting nanosystems. However, it is inefficient for emerging vancomycin-resistant species because of its poor affinity to the reprogrammed cell wall structure. This study demonstrates the use of a multivalent strategy as an effective way for overcoming such an affinity limitation in bacteria targeting. We designed a series of fifth generation (G5) poly(amidoamine) (PAMAM) dendrimers tethered with vancomycin at the C-terminus at different valencies. We performed surface plasmon resonance (SPR) studies to determine their binding avidity to two cell wall models, each made with either a vancomycin-susceptible (D)-Ala-(D)-Ala or vancomycin-resistant (D)-Ala-(D)-Lac cell wall precursor. These conjugates showed remarkable enhancement in avidity in the cell wall models tested, Including the vancomycin-resistant model, which had an increase in avidity of four to five orders of magnitude greater than free vancomycin. The tight adsorption of the conjugate to the model surface corresponded with Its ability to bind vancomycin-susceptible Staphylococcus aureus bacterial cells in vitro as imaged by confocal fluorescent microscopy. This vancomycin platform was then used to fabricate the surface of iron oxide nanoparticles by coating them with the dendrimer conjugates, and the resulting dendrimer-covered magnetic nanoparticles were demonstrated to rapidly sequester bacterial cells. In summary, this article investigates the biophysical basis of the tight, multivalent association of dendrimer-based vancomycin conjugates to the bacterial cell wall, and proposes a potential new use of this nanoplatform in targeting Gram-positive bacteria.