Enhancing Antibiotic-Resistant Bacterial Infection Therapy: Self-Assembling Gemini Quaternary Ammonium-Functionalized Peptide Nanoassemblies with Multiple Antibacterial Mechanisms

The rising threat of antimicrobial-resistant (AMR) infections highlights the urgent need for effective antimicrobial agents and therapies. Peptide-based antimicrobial nanomaterials are well-placed to meet this need. Here, we explore the conjugation of antimicrobial gemini quaternary ammonium compounds (GQAs) with designed short hexapeptides to create cationic antimicrobial nanomaterials with low cytotoxicity and minimal resistance tendency. (WA)₃GQA8C self-assembles into nanoparticles and exhibits potent antimicrobial activity against drug-resistant pathogens and enhanced stability. (WA)₃GQA8C protects against subcutaneous abscess infection and rescues mice from acute peritonitis infection by reducing the systemic bacterial burden and alleviating organ damage, with superior effects to vancomycin. Notably, (WA)₃GQA8C thoroughly disrupts bacterial membrane integrity akin to peeling fruit to induce bacterial membrane disintegration, a feat inaccessible to conventional antibiotics. Mechanistic studies suggest that (WA)₃GQA8C targets the bacterial membrane phospholipids phosphatidylglycerol (PG), inducing PG deformation to form fibrous or lamellar structures, which leads to the disruption of the bacterial membrane. Furthermore, the interference in lipoprotein trafficking exacerbates damage to bacterial membrane integrity. (WA)₃GQA8C also synergizes antimicrobial activity by impairing the protein synthesis function of the ribosome. These quaternized peptide nanoassemblies provide a rational strategy for designing peptide-based antimicrobial nanomaterials to combat the growing threats of resistant bacteria.