Nanoliposome mediated co-delivery of amoxicillin and tazobactam remediate intracellular infection by a multidrug-resistant Salmonella enterica serovar Typhimurium.

Abstract

Multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Typhimurium) poses a growing threat to food safety and animal health, particularly in the swine industry. In this study, we characterized a highly resistant ST strain isolated from a Quebec swine farm using whole-genome sequencing and phenotypic assays. The isolate harbored two plasmids, one of which encoded resistance to seven major antibiotic classes, including β-lactams, aminoglycosides, and sulfonamides, along with multiple virulence factors. To counteract these resistance mechanisms, we developed a nano-enabled antibacterial combination therapy (NeACT) by co-encapsulating amoxicillin (AMOX) and the β-lactamase inhibitor tazobactam into cyclodextrin encapsulated in liposomes (LP-CAT). Physicochemical analysis confirmed optimal particle size, charge, and stability, while checkerboard assays demonstrated strong drug synergism. The LP-CAT formulation drastically restored antimicrobial efficacy, reducing the AMOX minimum inhibitory concentration (MIC) from >2000 µg/mL to ~60 µg/mL. Using porcine intestinal epithelial (IPEC-J2) cells as an intracellular infection model, our study showed the potential of LP-CAT to remove >94% of intracellular bacteria with no cytotoxic effect. The ability of LP-CAT to resolve intestinal infection was further verified in Caenorhabditis elegans (C. elegans) intestinal infection model. These findings establish LP-CAT as a safe and effective strategy to revive antibiotic potency against intracellular MDR pathogens, offering a novel tool for combating antimicrobial resistance in livestock and safeguarding public health.