Nitazoxanide-Gold Nanoparticles Combat Carbapenem-Resistant Enterobacteriaceae via Membrane Disruption and Oxidative Stress.

Abstract

Carbapenem-resistant Enterobacteriaceae (CRE) pose a serious global health threat due to the ineffectiveness of conventional antibiotics, highlighting the need for new therapeutic strategies. This study explores the potential of nitazoxanide (NTZ), a clinically approved broad-spectrum antiparasitic drug, functionalized onto gold nanoparticles (AuNPs) as an antibacterial approach against CRE. NTZ_AuNPs were synthesized using a one-pot method, and their antibacterial efficacy was assessed through antimicrobial susceptibility testing, bacterial growth analysis, and electron microscopy. Biosafety was evaluated through hemolysis assays andmurine models. The NTZ_AuNPs showed significant bactericidal activity against CRE, with MICs ranging from 4 to 8 μg/mL, and exhibited favorable biocompatibility. Mechanistic investigations revealed that NTZ_AuNPs disrupt bacterial membranes, enhance outer membrane permeability, and infiltrate the intracellular environment. Additionally, NTZ_AuNPs increase reactive oxygen species (ROS) levels and impair bacterial ATP synthesis, suggesting a dual mechanism involving membrane disruption and oxidative stress. In a mouse model of abdominal infection, NTZ_AuNPs reduced bacterial burden and improved survival rates. These results validate the potential of NTZ_AuNPs as an effective, low-toxicity treatment for CRE infections, offering a promising alternative to traditional antibiotics.