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 compounds is promising in fighting bacterial infections. W e report a viable platform of metallopolymers as adjuvants in combination with traditional antibiotics to combat both planktonic and stationary phases of Gram-negative superbugs and their biofilms. Antibacterial efficacy, toxicity, anti-biofilm activity, bacterial resistance propensity, and mechanisms of action of metallopolymer-antibiotic combinations w ere investigated. These metallopolymers exhibited 4 to 16-fold potentiation of antibiotics against Gram-negative bacteria with negligible toxicity towards mammalian cells. More importantly, the lead combinations (polymer-ceftazidime and polymer-rifampicin) eradicated preformed biofilms of MDR E. coli and P. aeruginosa, respectively. Further, β-lactamase inhibition, outer membrane permeabilization, and membrane depolarization demonstrated synergy of these adjuvants with different antibiotics. Moreover, the membrane-active metallopolymers enabled the antibiotics to circumvent bacterial resistance development. Altogether, the results indicated that such non-antibiotic adjuvants bear the promise to revitalize the efficacy of existing antibiotics to tackle Gram-negative bacterial infections. This article is protected by copyright. All rights reserved.