The development of effective strategies against multidrug-resistant (MDR) pathogens is an urgent need in modern medicine. Nanoantibiotics (nABs) offer a new hope in countering the surge of MDR-pathogens. The aim of the current study was to evaluate the antibacterial activity of two attractive nABs, TiO2 NPs and ZnO NPs, and their performance in improving the antimicrobial activity of defined antibiotics (amoxicillin-clavulanic acid, amox-clav) against MDR-pathogens. The nABs were synthesized using a green method. The physicochemical characteristics of the synthesized nanoparticles were determined using standard methods. The results showed the formation of pure anatase TiO2 NPs and hexagonal ZnO NPs with an average particle size of 38.65 nm and 57.87 nm, respectively. The values of zeta potential indicated the high stability of the samples. At 8 mg/mL, both nABs exhibited 100% antioxidant activity, while ZnO showed significantly higher activity at lower concentrations. The antibiofilm assay showed that both nABs could inhibit the formation of biofilms of Acinetobacter baumannii 80 and Escherichia coli 27G (MDR-isolates). However, ZnO NPs showed superior antibiofilm activity (100%) against E. coli 27G. The MIC values were determined to be 8 (1), 2 (2), and 4 (4) mg/mL for amox-clav, TiO2 NPs, and ZnO NPs against A. baumannii 80 (E. coli 27G), respectively. The results showed that both nABs had synergistically enhanced antibacterial performance in combination with amox-clav. Specifically, an 8-fold reduction in MIC values of antibiotics was observed when they were combined with nABs. These findings highlight the potential of TiO2 NPs and ZnO NPs as effective nanoantibiotics against MDR-pathogens. The synergistic effect observed when combining nABs with antibiotics suggests a promising approach for combating antibiotic resistance. Further research and development in this area could lead to the development of more effective treatment strategies against MDR infections.

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