Co-delivery of nitric oxide and antibiotic using polymeric nanoparticles.

The rise of hospital-acquired infections, also known as nosocomial infections, is a growing concern in intensive healthcare, causing the death of hundreds of thousands of patients and costing billions of dollars worldwide every year. In addition, a decrease in the effectiveness of antibiotics caused by the emergence of drug resistance in pathogens living in biofilm communities poses a significant threat to our health system. The development of new therapeutic agents is urgently needed to overcome this challenge. We have developed new dual action polymeric nanoparticles capable of storing nitric oxide, which can provoke dispersal of biofilms into an antibiotic susceptible planktonic form, together with the aminoglycoside gentamicin, capable of killing the bacteria. The novelty of this work lies in the attachment of NO-releasing moiety to an existing clinically used drug, gentamicin. The nanoparticles were found to release both agents simultaneously and demonstrated synergistic effects, reducing the viability of Pseudomonas aeruginosa biofilm and planktonic cultures by more than 90% and 95%, respectively, while treatments with antibiotic or nitric oxide alone resulted in less than 20% decrease in biofilm viability.

Iron oxide nanoparticle-mediated hyperthermia stimulates dispersal in bacterial biofilms and enhances antibiotic efficacy.

The dispersal phase that completes the biofilm lifecycle is of particular interest for its potential to remove recalcitrant, antimicrobial tolerant biofilm infections. Here we found that temperature is a cue for biofilm dispersal and a rise by 5 °C or more can induce the detachment of Pseudomonas aeruginosa biofilms. Temperature upshifts were found to decrease biofilm biomass and increase the number of viable freely suspended cells. The dispersal response appeared to involve the secondary messenger cyclic di-GMP, which is central to a genetic network governing motile to sessile transitions in bacteria. Furthermore, we used poly((oligo(ethylene glycol) methyl ether acrylate)-block-poly(monoacryloxy ethyl phosphate)-stabilized iron oxide nanoparticles (POEGA-b-PMAEP@IONPs) to induce local hyperthermia in established biofilms upon exposure to a magnetic field. POEGA-b-PMAEP@IONPs were non-toxic to bacteria and when heated induced the detachment of biofilm cells. Finally, combined treatments of POEGA-b-PMAEP@IONPs and the antibiotic gentamicin reduced by 2-log the number of colony-forming units in both biofilm and planktonic phases after 20 min, which represent a 3.2- and 4.1-fold increase in the efficacy against planktonic and biofilm cells, respectively, compared to gentamicin alone. The use of iron oxide nanoparticles to disperse biofilms may find broad applications across a range of clinical and industrial settings.