The emergence and spread of antimicrobial resistance is a rapidly growing, global, healthcare threat. To counter this, new and innovative approaches to drug design are required. Synthetic cationic polymers and nanoparticles are particularly appealing as their composition and architecture can be finely tuned. In small molecule drug discovery, libraries with 1000’s of unique structures are standard, this is not the case yet in polymer chemistry, due to the need for exclusion of air and sealed vials creating a bottleneck in the discovery process. Considering the huge design space of polymers, there is clearly an urgent need to develop methods that explore this potential for new biomaterial discovery. For this to be possible, a high-throughput, robust, air-tolerant polymerization technique, with easy purification and facile transfer to screening platforms is required. To achieve this we employ a photochemical ‘in-air’ RAFT polymerization method in 96-well microtiter plates, using liquid handling robots to assemble large libraries of cationic polymers, without the need for degassing or purification steps, facilitating simple transfer to antimicrobial and cytotoxicity screening. This enables a &gt;100-member copolymer library to be assembled with excellent reproducibility and control over molecular weight. Several lead copolymers have been identified with up to 8-fold enhanced antimicrobial activity, and increased therapeutic window over the homopolymer. Mechanistic studies show this polymer is bacteriostatic and surprisingly does not lyse the cell membrane, implying an alternative mode of action to the homopolymer.

Combinatorial discovery of antimicrobial copolymers using ‘in-air’ photochemical RAFT polymerization

256th National Meeting (2018)

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