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 and in vivo murine 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.