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

Abstract

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 exhibit4-16-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 demonstratesynergy of these adjuvants with different antibiotics. Moreover, the membrane-active metallopolymers enablethe antibiotics to circumvent bacterial resistance development. Altogether, the results indicatethat such non-antibiotic adjuvants bear the promise to revitalize the efficacy of existing antibiotics to tackle Gram-negative bacterial infections.