Development of Sequence Controlled Polymers for Antibacterial Therapeutics and Co

描述（由申请人提供）：需要新的广谱抗生素来对抗多重耐药细菌是一个日益严重的全球性问题，对人类健康构成了合理的威胁。阳离子抗菌聚合物由于其低成本、广泛的潜在用途和不太容易产生耐药性的独特作用模式而代表了解决这一问题的有希望的方法。然而，这一领域的全面发展受到当前高分子化学的限制。虽然现代小分子药物化学有一系列工具来精确修饰和优化先导化合物，但受控聚合方法仍然依赖于一组相对较小的活性单体。该建议旨在通过开发一种新的序列程序化大环聚合策略，系统地评估这类抗生素的构效关系（SAR）。通过将受控聚合方法与快速闭环/开环反应相结合，构建了结构信息， 将被翻译到聚合物主链上，以提供对长序列具有空间控制并且可以引入化学多样性的明确定义的材料。该策略允许精确调节先前与抗菌活性有关的参数：阳离子基团的类型和数量、电荷密度、分子量和亲脂性。该研究将导致更好地了解与抗菌活性相关的结构特征，并将指导下一代聚合物治疗剂和涂层的设计，以提高效力和选择性。

DESCRIPTION (provided by applicant): The need for new broad-spectrum antibiotics to combat multidrug resistant bacteria is a growing global problem that poses a legitimate threat to human health. Cationic antibacterial polymers represent a promising approach to address this problem due to their low cost, wide range of potential uses and a distinct mode of action that is much less prone to the development of resistance. A full development of this area, though, has been hindered by the current limitations in polymer chemistry. Whereas modern medicinal chemistry for small molecules has an arsenal of tools to precisely modify and optimize lead compounds, controlled polymerization methods are still reliant on a relatively small set of competent monomers. This proposal aims to systematically evaluate the structure activity relationships (SAR) of this class of antibiotics through the development of a novel strategy for the polymerization of sequence-programmed macrocycles. By combining a controlled polymerization method with a rapid ring closing/ring opening reaction, structural information built into the macrocycle will be translated to the polymer backbone to provide well-defined materials that have spatial control over long sequences and can incorporate chemical diversity. This strategy allows for the precise modulation of parameters that have been previously implicated in antibacterial activity: type and number of cationic groups, charge density, molecular weight and lipophilicity. The research will result in a better understanding of the structural features associated with antibacterial activity and will guide the design of next generation polymer therapeutics and coatings with improved potency and selectivity.