Functionalized Polymers Enhance Permeability of Antibiotics in Gram-Negative MDR Bacteria and Biofilms for Synergistic Antimicrobial Therapy

The emergence of multidrug-resistant (MDR) pathogenic bacteria constitutes a key threat to global health. Infections caused by multidrug-resistant Gram-negative bacteria are particularly challenging to treat due to the ability of pathogens to prevent antibiotic penetration inside the bacterial membrane. Antibiotic therapy is further rendered ineffective due to biofilm formation where the protective extracellular polymeric substance matrix limits the diffusion of antibiotics inside the biofilm. It is hypothesized that careful engineering of chemical groups on polymer scaffolds can enable polymers to penetrate the barriers of Gram-negative bacterial membrane and biofilm matrix. Here, the use of engineered polymeric nanoparticles in combination with antibiotics for synergistic antimicrobial therapy is presented. These polymeric nanoparticles enhance the accumulation of antibiotics inside Gram-negative bacteria and the biofilm matrix, resulting in increased potency of antibiotics in combination therapy. Sublethal concentrations of engineered polymeric nanoparticles reduce the antibiotic dosage by 32-fold to treat MDR bacteria and biofilms. Tailoring of chemical groups on polymers demonstrates a strong structure-activity relationship in generating additive and synergistic combinations with antibiotics. This study demonstrates the ability of polymeric nanoparticles to "rejuvenate" antibiotics rendered ineffective by resistant bacteria and provides a rationale to design novel compounds to achieve effective antimicrobial combination therapies.