Introducing a new family of biodegradable antibacterial polymers: a structure-activity study Anna Constantinou 1 , David J. Peeler 1 , Sivaramesh Wigneshweraraj 2 , Molly M. Stevens 1 1 Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, UK, 2 Department of Infectious Diseases, Imperial College London, UK Antimicrobial resistance, i.e., resistance of bacteria to the action of antibiotics, caused by their misuse and overuse, is currently a major threat to human health. 1, 2 It is estimated that infectious diseases related to antimicrobial resistance will lead to ten million deaths per year by 2050, higher than any other major cause of death. 1 As it has been more than thirty years since a new family of antibiotics was introduced, 3 finding new ways to manage pathogenic bacteria is of great importance. Polymers, either natural or synthetic, with antibacterial properties are great candidates for addressing this issue. 4 Here, we present a new family of antibacterial polymers, synthesised by step-growth polymerisation, with a linear biodegradable backbone and tertiary amines bearing pendant hydroxy-alkyl side chains. To investigate the effect of hydrophobicity on polymer physicochemical and antibacterial properties, we tuned the side chain length from two to six carbons, thus creating a library of five polymers of equal molar mass. The antibacterial properties of these polymers against E. coli , the most common gram-negative pathogenic strain related to antimicrobial resistance, 2 have been extensively investigated. It has been shown that the minimum inhibitory concentration (MIC) is highly dependent on the length of the hydrophobic chain, with the MIC value reducing with increasing the hydrophobic side chain length. This indicates the tuneability of our material, which is key in achieving the desired properties needed for a future application. In addition, we have shown consistent toxicity of these new antimicrobial agents against E. coli that are in the lag, exponential, and stationary phases of growth. Alamar blue, lactate dehydrogenase release, and hemolysis assays with mammalian cells confirm polymer biocompatibility in both acute and chronic exposure settings due to rapid degradation, distinguishing these polymers from other polycationic antimicrobials established to date. These findings are promising for the development of new antimicrobial platforms that could assist in reducing the prevalent use of antibiotics and thus preserve their longevity. References 1. O'Neill, J. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations. The review on antimicrobial resistance (2014). 2. Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 339 , 629-655 (2022). 3. https://www.gov.uk/government/publications/health-matters-antimicrobial-resistance/health-matters-antimicrobial-resistance. 4. Haktaniyan, M. & Bradley, M. Polymers showing intrinsic antimicrobial activity. Chem. Soc. Rev. 51 , 8584-8611 (2022).
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