BSBE Seminar | Bacteriophages in Multidrug Resistant Infections: A Tale of Two Phages

Abstract:

Pseudomonas aeruginosa (Pa), an opportunistic pathogen particularly known for causing chronic wound and pulmonary infections, poses a significant challenge in clinical settings due to its intrinsic antibiotic resistance and biofilm-forming ability. There is a critical need for alternative therapeutic strategies. Bacteriophages (phages), both lytic and lysogenic, can infect and kill bacteria. We first examine the therapeutic potential of lytic phages, investigating the impact of dose, frequency, and administration route using a mouse wound infection model. Our findings indicate that local, topical delivery is superior to intravenous injection, with higher initial local doses significantly reducing bacterial burden, and repeated, daily dosing achieving the highest rates of eradication. Building on these insights, we developed “HydroPhage,” a hyaluronan-based hydrogel system that delivers high-titer phages over one week, eradicating infections up to five times more effectively than intravenous injection. We conclude that hydrogel-based sustained phage delivery enhances the efficacy of phage therapy and offers a practical, well-tolerated option for topical application. In parallel, we delve into the role of lysogenic Pf4 phages in exacerbating Pa infections and resistance mechanisms. Using fluorescent recovery after photobleaching (FRAP), we demonstrate that Pf4 interacts with anti-Pseudomonal antibiotics via charge-based electrostatic interactions. This interaction is further intensified by the formation of organized structures with airway sputum polymers, offering new insights into the complexities of phage-bacteria-antibiotic interactions in the context of multidrug-resistant infections.