Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria
Rational Design of Single-Chain Polymeric Nanoparticles That Kill Planktonic and Biofilm Bacteria
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DOI：
10.1021/acsinfecdis.6b00203
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发表时间：
2017-03-01
影响因子：
5.3
通讯作者：
Wong, Edgar H. H.
中科院分区：
文献类型：
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作者：
Thuy-Khanh Nguyen;Lam, Shu Jie;Wong, Edgar H. H.
由多重耐药细菌引起的感染正在增加，因此需要新的抗菌药物来防止后抗生素时代的到来。在这项研究中，我们开发了单链聚合物纳米粒子 (SCPN) 形式的新型抗菌化合物，该化合物在微摩尔浓度（例如 1.4 μM）下对革兰氏阴性菌（例如铜绿假单胞菌）表现出优异的抗菌活性，并且可显着杀死 99.99% 的浮游细胞和生物膜。 小时。线性无规共聚物包含低聚乙二醇 (OEG)、疏水基团和胺基团，由于分子内疏水相互作用，在水性体系中发生自折叠，产生这些 SCPN。通过系统地改变聚合物的疏水性，我们可以调节细胞膜壁破坏的程度，从而控制细菌的抗菌活性和耐药性获得率。我们还表明，将 OEG 基团纳入聚合物设计对于防止与生物介质中的蛋白质络合至关重要，从而即使在体内模拟条件下也能保持化合物的抗菌功效。与最后手段抗生素粘菌素相比，我们的主导药物具有更高的治疗指数（约 23 倍），因此具有更好的生物相容性。我们相信，这里开发的 SCPN 具有临床应用的潜力，并且有关其结构活性关系的信息对于合成抗菌（大）分子的总体设计将是有价值的。
Infections caused by multidrug-resistant bacteria are on the rise and, therefore, new antimicrobial agents are required to prevent the onset of a postantibiotic era. In this study, we develop new antimicrobial compounds in the form of single-chain polymeric nanoparticles (SCPNs) that exhibit excellent antimicrobial activity against Gram-negative bacteria (e.g., Pseudomonas aeruginosa) at micromolar concentrations (e.g., 1.4 mu M) and remarkably kill =99.99% of both planktonic cells and biofilm within an hour. Linear random copolymers, which comprise oligoethylene glycol (OEG), hydrophobic, and amine groups, undergo self-folding in aqueous systems due to intramolecular hydrophobic interactions to yield these SCPNs. By systematically varying the hydrophobicity of the polymer, we can tune the extent of cell membrane wall disruption, which in turn governs the antimicrobial activity and rate of resistance acquisition in bacteria. We also show that the incorporation of OEG groups into the polymer design is essential in preventing complexation with proteins in biological medium, thereby maintaining the antimicrobial efficacy of the compound even in in vivo mimicking conditions. In comparison to the last-resort antibiotic colistin, our lead agents have a higher therapeutic index (by ca. 23 times) and hence better biocompatibility. We believe that the SCPNs developed here have potential for clinical applications and the information pertaining to their structureactivity relationship will be valuable toward the general design of synthetic antimicrobial (macro)molecules.