(99b) Treatment of Gram-Negative Bacteria Using Stimuli-Responsive Nanoantibiotics

In 2017, the World Health Organization confirmed that the world is running into a global crisis of antibiotic resistant bacteria. The clinical pipelines for antibiotics are few and even the chemicals in development are small modifications that are only short-term solutions to the problem We propose developing a platform using a unique combination of nanoparticles, conventional antibiotics and gene therapy to combat the rising antibiotic resistance problem. Our core technology is acid-transforming chitosan (ATC), a stimuli-responsive modification of chitosan that serves as the nanoantibiotic and delivery vehicle. We explored the antimicrobial capabilities of ATC and determined the possible mechanism for its antimicrobial efficacy. We determined the antimicrobial efficacy against various strains of three gram-negative pathogens (E. coli, S. typhimurium, and P. aeruginosa). These pathogens are commonly resistant to many antibiotics (beta-lactams, macrolides, tetracyclines, co-trimoxazole, and most fluoroquinolones), and has they have the capacity to develop resistance to a wide range of antimicrobials. ATC polymer was tested at varying pH conditions and we observed a positive correlation between pH and the polymer efficacy against the microbe. Additionally, ATC/fDNA polyplexes were applied to RAW 264.7 cells co-infected with S. typhimurium expressing GFP this resulted in a decrease in the levels of bacteria found within the cells as confirmed by flow cytometry. Furthermore, ATC/Ciprofloxacin nanoparticles were created by ionic gelation and their synergistic efficacy was observed. Overall, our results indicate that these nanoantibiotics provide an effective alternate strategy to treat bacterial infections.