Novel synergistic activities of tetracycline copper oxide nanoparticles integrated into chitosan micro particles for delivery against multiple drug resistant strains: Generation of reactive oxygen species (ROS) and cell death

Abstract

One of the main strategies on the antibiotic resistance is the synergy between antibiotics and nanoparticles either free or integrated into carriers and slow release. Copper oxide nanoparticles (CuONp) and chitosan microparticles (CsMp) were synthesized by chemical precipitation and ionic gelation method, respectively. CuONp was integrated into the CsMp by sonication method and denoted as CsMp@CuONp. The results revealed the uniform distribution of copper oxide nanoparticles in chitosan matrix with an average size of 8 nm and 1 μm for CuONp and CsMp, respectively. The antibacterial and blood compatibility of CuONp and the synergistic studies of tetracycline/CuONp and tetracycline/CsMp@CuONp were investigated. The average fractional inhibitory concentration (FIC) of tetracycline with CuONp was 0.85 and for tetracycline with CsMp@CuONp reduced to 0.44 which indicated the additive and synergic effect respectively. The generation of reactive oxygen species (ROS) as the primary cause of nanotoxicity and bacterial cell death were achieved by 30 ppm and 60 ppm copper oxide nanoparticles for Gram positive and Gram negative strains respectively. CsMp@CuONp has a greater synergic effect for antibacterial activity of tetracycline compared with CuONp. The CuONp shows interaction with antibiotic and act as tetracycline carrier with enhanced its accumulation interacted with bacteria. The integration of CuONp into the CsMp resulted in blood compatibility at concentrations below 60 ppm.