Novel Antimicrobials and Drug Delivery Devices to Treat Multidrug Resistant Infections

Abstract

The discovery and development of antibiotics in the early 20th century led to a significant reduction in mortality from infectious diseases. However, the age of antibiotics has coincided with the accelerated emergence of antimicrobial resistance (AMR). Bacteria, armed with diverse resistance mechanisms, began developing resistance to antibiotics immediately after their deployment and sometimes even during the development process. In fact, the AMR crisis has reached a critical point, where bacteria have become multidrug resistant (MDR) rendering even the last-resort antibiotics in our arsenal impotent. Specifically, bacterial infections from ESKAPE pathogens have become paradigms of infection and resistance. The research presented in this study utilized three strategies that have the potential to address the AMR crisis and improve human health: 1) identification of novel compounds from different ecological niches, 2) repurposing and combining drugs, and 3) use of nanosized drug delivery systems. Particularly, pulmonary and chronic wound infections from P. aeruginosa and S. aureus will be studied to evaluate the strategies used to address the AMR crisis. First, a known antibiotic, ciprofloxacin, was encapsulated within liposomes functionalized with targeting moieties to deliver the drug directly to the site of infection. Utilizing a murine infection model, a significant survival advantage was observed in mice treated with targeted ciprofloxacin-liposomes compared to nontargeted ciprofloxacin liposomes. Then, we assessed novel compounds for antimicrobial efficacy, alone and in combination, against R. equi, an equine pathogen that causes pneumonia in foals. Specifically, a combination treatment of a novel antimicrobials, gallium maltolate (GaM) and C58, isolated from marine bacterium, has demonstrated antimicrobial efficacy against intracellular R. equi. Similarly, C58 loaded nanoparticles, along with GaM treatment also significantly reduced the bacterial burden of intracellular R. equi. Finally, using silver nitrate and ibuprofen we synthesized the silver salt of ibuprofen (Ag+IBU). This novel compound synthesized from old drugs, has demonstrated broad-spectrum antimicrobial efficacy while exhibiting no cytotoxicity at therapeutic concentrations. A multi-step resistance acquisition study revealed that over 21 days of subculturing and treatment with Ag+IBU did not lead to the development of resistance in P. aeruginosa or S. aureus strains, PAO1 and USA 300, respectively. Furthermore, Ag+IBU was encapsulated within nanoparticles and incorporated in electrospun scaffolds to allow for targeted treatment of pulmonary and chronic wound infections, respectively. The research presented here demonstrates the importance of exploring novel strategies to address the AMR crisis and once again, gain superiority over infectious diseases.