Phage-Mimicking Nanoparticles Conjugated with Antimicrobial Peptides and Polymers as an Alternative to Antibiotic Treatment

The development of antibiotic resistance and the resulting emergence of multidrug-resistant bacteria has become one of the main threats in the public health system, commonly leading to nosocomial infections and implant-associated infections that are very challenging to treat. This thesis is based on the antibiotic-free phage-mimicking nanoparticle (PhaNP) system developed by our lab to fight antibiotic-resistant bacterial infections. Here, PhaNP design is improved by conjugating various antimicrobial peptides (AMPs) and antimicrobial polymers to develop potential medical applications, in liquid and immobilized phases, as alternatives to antibiotics. First, various PhaNP and AMP combinations (PhaNP@Peptide) against several clinically relevant antibiotic-resistant Gram-positive and Gram-negative bacteria strains are tested to investigate and compare their antibacterial activity, results displaying high inhibition of the bacteria by PhaNP@Peptide, irrespective from the Gram group. Further, we study the antibacterial effect of Syn71 peptide-modified PhaNPs (PhaNP@Syn71) tested in vitro and in vivo against Streptococcus pyogenes. The results show a high antibacterial activity of PhaNP@Syn71 against the bacteria while exhibiting low cytotoxicity to mammalian cells, both in in vivo and in vitro studies, suggesting a strong potential of peptide-conjugated PhaNPs as a highly effective antibacterial system that can potentially combat S. pyogenes bacterial infections. Finally, PhaNPs are tested in an immobilized phase on metal implant materials, and their further conjugation with branched and linear antimicrobial polymers to create antibacterial coatings. The antibacterial effect of the coatings is tested in vitro on Staphylococcus aureus USA300 and Pseudomonas aeruginosa FRD1, with results displaying a great antibacterial effect of the coating compared to the unmodified metal implant. Overall, in this work, we successfully show the potential of the improved PhaNP design conjugated with various AMPs and antimicrobial polymers to be used as an alternative to conventional antibiotic treatment of bacterial infections and in the prevention of implant-associated infections.