Cerium oxide nanoparticles as potential antibiotic adjuvant. Effects of CeO2nanoparticles on bacterial outer membrane permeability

Background: Therapeutic options against Multi Drug Resistant (MDR) pathogens are limited and the overall strategy would be the development of adjuvants able to enhance the activity of therapeutically available antibiotics. Non-specific outer membrane permeabilizer, like metal-oxide nanoparticles, can be used to increase the activity of antibiotics in drug-resistant pathogens. The study aims to investigate the effect of cerium oxide nanoparticles (CeO2NPs) on bacterial outer membrane permeability and their application in increasing the antibacterial activity of antibiotics against MDR pathogens. Methods: The ability of CeO2NPs to permeabilize Gram-negative bacterial outer membrane was investigated by calcein-loaded liposomes. The extent of the damage was evaluated using lipid vesicles loaded with FITC-dextran probes. The effect on bacterial outer membrane was evaluated by measuring the coefficient of permeability at increasing concentrations of CeO2NPs. The interaction between CeO2NPs and beta-lactams was evaluated by chequerboard assay against a Klebsiella pneumoniae clinical isolate expressing high levels of resistance against those antibiotics. Results: Calcein leakage increases as NPs concentrations increase while no leakage was observed in FITC-dextran loaded liposomes. In Escherichia coli the outer membrane permeability coefficient increases in presence of CeO2NPs. The antibacterial activity of beta-lactam antibiotics against K. pneumoniae was enhanced when combined with NPs. Conclusions: CeO2NPs increases the effectiveness of antimicrobials which activity is compromised by drug resistance mechanisms. The synergistic effect is the result of the interaction of NPs with the bacterial outer membrane. The low toxicity of CeO2NPs makes them attractive as antibiotic adjuvants against MDR pathogens.