Caffeine and Cationic Copolymers with Antimicrobial Properties

[Image: see text] One of the primary global health concerns is the increase in antimicrobial resistance. Polymer chemistry enables the preparation of macromolecules with hydrophobic and cationic side chains that kill bacteria by destabilizing their membranes. In the current study, macromolecules are prepared by radical copolymerization of caffeine methacrylate as the hydrophobic monomer and cationic- or zwitterionic-methacrylate monomers. The synthesized copolymers bearing tert-butyl-protected carboxybetaine as cationic side chains showed antibacterial activity toward Gram-positive bacteria (S. aureus) and Gram-negative bacteria (E. coli). By tuning the hydrophobic content, we prepared copolymers with optimal antibacterial activity against S. aureus, including methicillin-resistant clinical isolates. Moreover, the caffeine–cationic copolymers presented good biocompatibility in a mouse embryonic fibroblast cell line, NIH 3T3, and hemocompatibility with erythrocytes even at high hydrophobic monomer content (30–50%). Therefore, incorporating caffeine and introducing tert-butyl-protected carboxybetaine as a quaternary cation in polymers could be a novel strategy to combat bacteria.