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 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