Biguanide-Derived Polymeric Nanoparticles Kill MRSA Biofilm and Suppress Infection in Vivo

Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of drug-resistant infections. Its propensity to develop biofilms makes it especially resistant to conventional antibiotics. We present a novel nanoparticle (NP) system made from biocompatible F-127 surfactant, tannic acid (TA), and biguanide-based polymetformin (PMET) (termed FTP NPs), which can kill MRSA biofilm bacteria effectively in vitro and in vivo and which has excellent biocompatibility. FTP NPs exhibit biofilm bactericidal activity - ability to kill bacteria both inside and outside biofilm - significantly better than many antimicrobial peptides or polymers. At low concentrations (8-32 μg/mL) in vitro, FTP NPs outperformed PMET with ∼100-fold (∼2 log₁₀) greater reduction of MRSA USA300 biofilm bacterial cell counts, which we attribute to the antifouling property of the hydrophilic poly(ethylene glycol) contributed by F-127. Further, in an in vivo murine excisional wound model, FTP NPs achieved 1.8 log₁₀ reduction of biofilm-associated MRSA USA300 bacteria, which significantly outperformed vancomycin (0.8 log₁₀ reduction). Moreover, in vitro cytotoxicity tests showed that FTP NPs have less toxicity than PMET toward mammalian cells, and in vivo intravenous injection of FTP NPs at 10 mg/kg showed no acute toxicity to mice with negligible body weight loss and no significant perturbation of blood biomarkers. These biguanide-based FTP NPs are a promising approach to therapy of MRSA infections.