The resistance of many bacteria against currently available antimicrobial agents is increasing worldwide at an alarming pace. The described structure–activity relationship study was prompted by the extraordinary ability of water-dispersed microgels to hydrolyze glycosidic bonds similar to building blocks of the peptidoglycan layer of Gram-positive bacteria. The results establish polyacrylate microgels with embedded copper­(II) complex as antimicrobial agents. The systematic study reveals that Staphylococcus aureus is susceptible to the microgels, while common commercial agents are found intermediate or resistant. In particular, a microgel with 60 mol % of cross-linking, Cu 2 LP60%, shows intriguing bactericidal activity at 1 μg/mL, while vancomycin requires a 4-fold higher dose, i.e., 4 μg/mL, for the same effect. The minimum inhibitory concentration of Cu 2 LP60% was determined as low as 0.64 μg/mL. Excellent stability of the poly­(acrylate) microgels was observed by negative zeta potentials in nanopure water and aqueous sodium dodecyl sulfate solution. The composition of the microgel matrix with embedded binuclear metal complex was shown to be responsible for the antimicrobial activity, while the aqueous buffer–surfactant solution is not.

Emerging infections of unknown origin and increasing bacterial resistance against available antibiotics necessitate the development of different antimicrobial agents with unconventional mechanisms of action. A promising strategy to meet this need may be found by combining polymeric scaffolds with transition metals, e.g., by decorating polyacrylate-based microgels with Cu(II) complexes. A series of structure−activity relationship studies using broth microdilution assays with such materials and Staphylococcus aureus concluded that the antimicrobial activity of microgels can be tailored during their synthesis by choice of co-monomers, by design of the binding strength between Cu(II) ions and backbone ligands, and by selection of the counter ions for coordination to the metal complexes. A microgel Cu 2 L P(EG) (L = VBbsdpo) with an optimized minimal inhibitory concentration of 0.39 ± 0.03 μg/mL is thereby derived and synthesized from 60 mol % of cross-linking ethylene glycol dimethacrylate, 40 mol % butyl acrylate, 0.5 mol % VBbsdpo ligand with 1 mol % Cu(II) ions, and 5 mol % ethylene glycol as counter ions. The antimicrobial activity of the microgel has a lifetime of over 18 months at ambient temperature. Bactericidal activity of the same microgel is observed by replating assays in less than 15 min when exposing S. aureus to microgel concentrations of 1.5-fold of its minimum inhibitory concentration (MIC) value or higher. Furthermore, spectrophotometric evaluations at 260 nm revealed time-and concentration-dependent release of intracellular bacterial components after interactions with the microgel indicating irreversible damage to the bacterial cell membrane as a possible mechanism of activity. Preliminary results indicate that the selected microgels are not cytotoxic toward human dermal fibroblasts at MIC value concentrations for over 20 h.