Photochemical “In‐Air” Combinatorial Discovery of Antimicrobial Co‐polymers

• Published in: Chemistry : a European journal 2018-09, Vol.24 (52), p.13758-13761
• Main Authors: Richards, Sarah‐Jane, Jones, Adam, Tomás, Ruben M. F., Gibson, Matthew I.
• Format: Article
• Language: English
• Subjects: Addition polymerization; Anti-Bacterial Agents - chemical synthesis; Antiinfectives and antibacterials; Antimicrobial activity; Antimicrobial agents; antimicrobials; Automation; bacteria; Biomaterials; Biomedical materials; Cationic polymerization; Cations; Cell membranes; Chemistry; Combinatorial analysis; combinatorial chemistry; Communication; Communications; Degassing; Drug Evaluation, Preclinical; Escherichia coli - drug effects; Humans; Light; Manufacturing engineering; Membranes; Methacrylates - chemistry; Mode of action; Mycobacterium - drug effects; Organic chemistry; Photochemical Processes; Photochemicals; Polymerization; Polymers; Polymers - chemical synthesis; Propylene; Propylene glycol; Purification; Small Molecule Libraries - chemical synthesis
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201802594

There is an urgent need to identify new, non‐traditional antimicrobials. The discovery of new polymeric antimicrobials is limited by current low‐throughput synthetic tools, which means that limited chemical space has been explored. Herein, we employ photochemical “in‐air” reversible addition–fragmentation chain‐transfer (RAFT) polymerization with microwell plates, using liquid‐handling robots to assemble large libraries of cationic polymers, without the need for degassing or purification steps, facilitating transfer to screening. Several lead polymers were identified including a co‐polymer with propylene glycol side chains with significantly enhanced antimicrobial activity and increased therapeutic window. Mechanistic studies showed that this polymer was bacteriostatic, and surprisingly did not lyse the cell membranes, implying an alternative mode of action. This versatile method using simple robotics will help to develop new biomaterials with emergent properties. Non‐traditional antimicrobial discovery: A library‐oriented approach for in‐air photo‐reversible addition–fragmentation chain‐transfer (RAFT) polymerization is employed to create a library of cationic polymers, which were screened to identify leads with antimicrobial activity. The most active polymers were found to be bacteriostatic, rather than membrane lytic, and the most active were not the most hydrophobic implying a new mechanism of action and leads for new antimicrobial agents (see figure).