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.
Antibacterial polymers have tremendous potential as broad-spectrum agents to combat the growing problem of multidrug resistance, both in the body and on everyday surfaces. The proposed research will develop novel strategies for the modular synthesis these polymers that allows for precise control over sequence and structure. An increased understanding of the structural requirements for antibacterial activity will lead to the design of superior therapeutics and coatings for the improvement of human health.