Niclosamide nanoparticles as a novel adjuvant reverse colistin resistance via multiple mechanisms against multidrug-resistant Salmonella infections.

The mobile colistin resistance (mcr) mechanism enables rapid horizontal transfer of resistance genes across food, animals, and humans, driving significant resistance in mcr-carrying bacteria. While numerous adjuvants can reverse colistin resistance, research on their dose-response relationships remains limited, and most suffer from poor solubility, low bioavailability, and safety issues, hindering clinical use. The dose-response analysis showed that niclosamide could achieve a high reversal efficiency within a relatively low concentration range. However, as the concentration of niclosamide increased, the ability to reverse colistin resistance remained unchanged, and the reversal efficiency gradually decreased. Mechanistic analyses reveal that its synergistic antibacterial effect with colistin involves disrupting bacterial membrane permeability, dissipating proton motive force, and inhibiting efflux pumps, leading to membrane damage, cytoplasmic leakage, ATP depletion, and accelerated reactive oxygen species-mediated oxidative damage, ultimately resulting in the death of bacterial cells. A niclosamide nanodelivery system (niclosamide-loaded mPEG-PLGA nanoparticles [NCL@mPEG-PLGA-NPs]) was developed to enhance bioavailability, significantly boosting colistin's efficacy against Salmonella in vitro and in vivo. The in-depth study of the dose-response relationship of adjuvants in reversing colistin resistance and the establishment of the niclosamide nanodrug delivery system will lay a scientific foundation for the clinical application of colistin adjuvants and the development of suitable drug delivery systems.

Importance: Colistin is used as a last resort for many infections caused by multidrug-resistant gram-negative bacteria, but colistin-resistant strains are on the rise. Studies have found that the combination of niclosamide and colistin exhibits significant synergistic antibacterial effects. Dose-response analysis shows that niclosamide has extremely high resistance reversal efficiency within a relatively low concentration range. The development of the new dosage form of NCL@mPEG-PLGA-NPs will lay a scientific foundation for the clinical application of colistin adjuvants and the development of drug delivery systems.