Membrane‐Active Metallopolymers: Repurposing and Rehabilitating Antibiotics to Gram‐Negative Superbugs

Among multiple approaches to combating antimicrobial resistance, a combination therapy of existing antibiotics with bacterial membrane‐perturbing agents is promising. A viable platform of metallopolymers as adjuvants in combination with traditional antibiotics is reported in this work to combat both planktonic and stationary cells of Gram‐negative superbugs and their biofilms. Antibacterial efficacy, toxicity, antibiofilm activity, bacterial resistance propensity, and mechanisms of action of metallopolymer‐antibiotic combinations are investigated. These metallopolymers exhibit 4‐16‐fold potentiation of antibiotics against Gram‐negative bacteria with negligible toxicity toward mammalian cells. More importantly, the lead combinations (polymer‐ceftazidime and polymer‐rifampicin) eradicate preformed biofilms of MDR E. coli and P. aeruginosa, respectively. Further, β‐lactamase inhibition, outer membrane permeabilization, and membrane depolarization demonstrate synergy of these adjuvants with different antibiotics. Moreover, the membrane‐active metallopolymers enable the antibiotics to circumvent bacterial resistance development. Altogether, the results indicate that such non‐antibiotic adjuvants bear the promise to revitalize the efficacy of existing antibiotics to tackle Gram‐negative bacterial infections. The cationic cobaltocenium‐containing polymer is a potentiating adjuvant, which shows less inhibition against Gram‐negative superbugs but can rejuvenate the efficacy of common antibiotics. Antibacterial efficacy, toxicity, antibiofilm activity, bacterial resistance propensity, and mechanisms of action of metallopolymer‐antibiotic combinations are investigated. More importantly, the cationic metallopolymer in combination with antibiotics disrupts preformed biofilms of Gram‐negative bacteria.