Antimicrobial cobaltocenium copolymers: tuning amphiphilicity against NDM-1 bacteria

The emergence of Gram-negative superbugs coupled with a steep decline in antibiotic pipelines has imposed a serious threat to global public health. Cationic metallopolymers have gained significant attention due to their antimicrobial efficacy. In this work, we developed a range of broad-spectrum antimicrobial cobaltocenium and ammonium containing copolymers with different compositions, which attain the amphiphilic balance without compromising the total charges for enhanced interaction with bacterial membranes. The copolymers showed high antimicrobial efficacy with greater selectivity than the corresponding ammonium-containing methacrylate polymers. The mechanistic investigations of the lead polymer using bacterial strains harboring the New Delhi metallo-β-lactamase (NDM-1) enzyme revealed its membrane-active nature. The copolymer with 69% dimethyl cobaltocenium showed a minimal increase in the minimal inhibitory concentration over 14 passages, whereas polymyxin-B showed a 256-fold increase. These findings provided insights into metallopolymers with optimal amphiphilicity as potent antimicrobial agents to tackle Gram-negative superbugs.