Materials Science and Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States.
Curr Pharm Des. 2018;24(8):855-865. doi: 10.2174/1381612824666180213140732.
The rising incidence of antibiotic-resistant infections, combined with a declining number of new antibiotic drug approvals, has generated an alarming therapeutic gap that critically undermines public health. Host Defense Peptides (HDPs), sometimes referred to as "Nature's Antibiotics", are short chain, amphiphilic and cationic peptide sequences found in all multicellular organisms as part of their innate immunity. While there is a vast diversity in terms of HDP sequence and secondary structure, they all seem to share physiochemical characteristics that can be appropriated for macromolecular design by the synthetic polymer chemist. Over the past decade, remarkable progress has been made in the design and synthesis of polymer-based materials that effectively mimic HDP action - broad-spectrum antibacterial potency, rapid bactericidal kinetics, and minimal toxicity to human cells - while offering the additional benefits of low cost, high scalability, and lower propensity to induce resistance, relative to their peptide-based counterparts. A broad range of different macromolecular structures and architectures have been explored in this design space, including polynorbornenes, poly(meth)acrylates, poly(meth)acrylamides, nylon-2 polymers, and polycarbonates, to name a just few. Across all of these diverse chemical categories, the key determinants of antibacterial and hemolytic activity are the same as in HDPs: net cationic charge at neutral pH, well-balanced facial amphiphilicity, and the molecular weight of the compounds. In this review, we focus in particular on recent progress in the polymethacrylate category first pioneered by Kuroda and DeGrado and later modified, expanded upon and rigorously optimized by Kuroda's and many other groups. Key findings and future challenges will be highlighted.
抗生素耐药性感染的发病率不断上升，而新批准的抗生素药物数量却在减少，这造成了令人震惊的治疗缺口，严重威胁着公共卫生。宿主防御肽（HDPs），有时也被称为“天然抗生素”，是在所有多细胞生物中发现的短链、两亲性和阳离子肽序列，是其先天免疫的一部分。虽然 HDP 序列和二级结构有很大的多样性，但它们似乎都具有可以被合成聚合物化学家用于大分子设计的物理化学特性。在过去的十年中，在设计和合成聚合物基材料方面取得了显著进展，这些材料有效地模拟了 HDP 的作用——广谱抗菌效力、快速杀菌动力学和对人类细胞的最小毒性——同时提供了低成本、高可扩展性和降低诱导耐药性倾向的额外好处，与它们的肽基对应物相比。在这个设计空间中，已经探索了广泛的不同的大分子结构和架构，包括聚降冰片烯、聚（甲基）丙烯酸酯、聚（甲基）丙烯酰胺、尼龙-2 聚合物和聚碳酸酯等等。在所有这些不同的化学类别中，抗菌和溶血活性的关键决定因素与 HDP 相同：中性 pH 下的净正电荷、平衡的面两亲性和化合物的分子量。在这篇综述中，我们特别关注 Kuroda 和 DeGrado 首先开创的聚甲基丙烯酸酯类别中的最新进展，随后 Kuroda 和许多其他小组对其进行了修改、扩展和严格优化。我们将重点介绍关键发现和未来挑战。
