Development of Sequence Controlled Polymers for Antibacterial Therapeutics and Co

描述(申请人提供)：需要新的广谱抗生素来对抗多重耐药细菌，这是一个日益严重的全球问题，对人类健康构成了合法的威胁。阳离子抗菌聚合物由于其低成本、广泛的潜在用途以及不容易产生耐药性的独特的作用模式，是解决这一问题的一种有前途的方法。然而，目前聚合物化学的局限性阻碍了这一领域的充分发展。虽然现代小分子药物化学拥有大量工具来精确修饰和优化先导化合物，但可控聚合方法仍然依赖于相对较少的合格单体。这项建议旨在通过开发一种新的序列编程大环聚合策略来系统地评价这类抗生素的构效关系(SAR)。通过将受控聚合方法与快速合环/开环反应相结合，建立了结构信息 进入大循环的物质将被转化到聚合物主干上，以提供定义明确的材料，这些材料对长序列具有空间控制，并可以结合化学多样性。这一策略允许对先前涉及抗菌活性的参数进行精确调节：阳离子基团的类型和数量、电荷密度、分子量和亲脂性。这项研究将有助于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疗法和涂层的设计，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.