Overuse of antibiotics has created “superbugs” such as methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) that pose serious threat to global health due to treatment failure and high mortality rates. The threat is further aggravated by chronic infections from biofilms, which exhibit high resistance towards both the host immune response and traditional antimicrobial therapy. Synthetic macromolecules have emerged as an alternative to conventional antibiotic therapy exhibiting broad spectrum activity against antibiotic-resistant bacteria. However, high toxicity towards mammalian cells and concomitant low therapeutic indices have limited their practical applications in clinical settings. Here, we report engineered polymers that can effectively eradicate pre-formed biofilms while maintaining a high therapeutic index against human red blood cells (RBCs). We synthesized a library of quaternary ammonium poly(oxanorborneneimides) possessing different degrees of hydrophobicity and screened their antimicrobial and hemolytic activities. These polymers form 10-15 nm nanoparticles in aqueous solution, increasing their overall cationic charge and molecular mass. We determined that increasing hydrophobicity of the alkyl chains bridging the cationic head group and polymer backbone greatly enhances toxicity against planktonic bacteria while maintaining excellent hemolytic activities towards RBCs (Therapeutic Index &gt;5000). Additionally, polymeric nanoparticles readily penetrate and eradicate pre-formed biofilms while still maintaining high therapeutic indices (~120) relative to RBCs. Polymeric NPs demonstrated a 6-log reduction in bacterial count in a biofilm-mammalian cell coculture model. Significantly, we observed that bacteria did not develop any resistance against polymeric NPs even after 20 serial passages. Overall, our engineered polymeric nanoparticle platform shows strong potential as an infectious disease therapeutic and simultaneously provides a rational approach to design novel antimicrobials for long-term combating of bacterial infections.

Functionalized polymeric nanoparticles for the treatment of MDR bacteria and biofilm infections

256th National Meeting (2018)

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