细菌微环境响应高分子抗菌剂的构筑、纳米结构调控与协同抗菌研究

Macromolecular antimicrobials possess the advantages of enduring antibacterial activities, environmental friendship and low toxicity to human and so on. Conventional macromolecular antimicrobials are mainly focused on the feature of positive charge and amphiphilicity to realize antibacterial effects, only exhibiting limited antibacterial activities, and it is rare to find the involvement of bacterial microenvironment-responsive release of active small molecular antimicrobials as well as the participation of various nanostructures fabricated from macromolecular antimicrobials, which would probably achieve synergetic antibacterial effects to enhance antibacterial activities. In this funding proposal, we attempt to explore the fabrication, nanostructural tuning and synergetic antibacterial effects of bacterial microenvironment-responsive macromolecular antimicrobials. Firstly, three kinds of hydrophobic small molecular broad-spectrum antimicrobials are selected to synthesize six types of antimicrobial prodrug monomers which are biologically responsive to reductive compounds or Beta-lactamases in bacterial microenvironments. Followed by controlled polymerization and functionalization with targeting ligands, a series of bacterial microenvironment-responsive macromolecular antimicrobials were synthesized. Then, various nanostructures of the resultant macromolecular antimicrobials will be fabricated via molecular self-assembly. Finally, we will explore the nanostructural shape effects of macromolecular antimicrobials on synergetic antibacterial activities, selectivity, and cellular interactions, aiming to optimize the antibacterial performance and safety concerns. The accomplishment of this proposed research is expected to significantly enhance the antibacterial effect and safety of synthetic macromolecular antimicrobials and understand the relationship among chemical compositions, nanostructures and antibacterial effects, providing an important reference for the construction of new generation functional macromolecular antimicrobial systems.

高分子抗菌剂具有抗菌时效长，环境污染小，人体伤害低等优势。传统高分子抗菌剂主要利用正电荷和两亲性特征进行抗菌，抗菌活性一般；结合细菌微环境刺激释放活性小分子抗菌剂及其多级纳米结构调控，进行协同抗菌有望提高抗菌效果，却鲜有涉及。本项目拟探索细菌靶向修饰、细菌微环境响应高分子抗菌剂的构筑、纳米结构调控与协同抗菌效应。首先选取三种疏水的小分子广谱抗菌剂，结合很多细菌的还原性和Beta-内酰胺酶微环境特征，制备响应性抗菌剂前药单体，经过可控聚合和细菌靶向基元修饰,合成系列细菌微环境响应高分子抗菌剂；其次，利用自组装构筑多种纳米结构；最后研究不同纳米结构高分子抗菌剂的协同抗菌活性、选择性及与细菌的相互作用，以实现最佳抗菌效果和更高选择性。该项目的实施将有助于增强高分子抗菌剂的抗菌效果和安全性，并理解高分子抗菌剂的化学组成、纳米结构与抗菌效应的关系，为下一代功能性高分子抗菌体系的设计提供重要参考。

两亲性高分子具有很多生物功能，如作为药物载体。其自身还可以模拟抗菌肽表现出抗菌性能，同时具有容易制备，抗菌时效长，环境污染小，人体伤害低等优势。依托本项目支持在响应性高分子抗菌和肿瘤诊疗领域都取得重要进展。署名本项目的第一作者/通讯作者论文15篇：包括10篇SCI论文，影响因子大于7.0的SCI论文7篇，JACS 1篇，Trends in Biotechnology 1篇， Biomaterials 3篇，ACS Appl. Mater. Interfaces 1篇，J. Control. Release 1篇。