Advancing Phage Therapy through Synergistic Strategies: Phage-Mediated Killing and Competitive Exclusion using Engineered Prophages

Amid the antibiotic resistance crisis, the century-old practice of phage therapy, the use of bacterial viruses to treat bacterial infections, has gained renewed attention. Despite extensive research and clear-cut advantages over antibiotics, phage therapy has yet to gain momentum. This is primarily due to remaining limitations, e.g., the time-consuming process of identifying suitable phages and limited in vivo efficacy. With PHAGE-PRO I propose a new technology to overcome the shortcomings of traditional phage therapy. Unlike the conventional use of lytic phages, I will capitalize on prophages – viruses that integrate into bacterial genomes capable of excision and replication. By integrating prophages into safe carrier strains, originating from probiotics, I will unlock two pivotal benefits, (1) rapid identification of suitable phages using advanced machine learning, (2) sustained in-vivo efficacy. Yet, the core advantage of PHAGE-PRO lies in its unparalleled synergy of phage killing and pathogen competitive exclusion imposed by the probiotic.To realize this concept, the development of predictive tools is essential to quickly identify the most promising prophages and probiotic combinations for each pathogen (WP1). Prophage engineering (WP2), followed by rigorous in vitro testing will ensure a high safety and efficacy. High-throughput in vivo experiments using wax moth larvae will reveal the most promising candidate which I will subsequently validate through a proof of principle experiment using a poultry model (WP3).Although I initially tailored PHAGE-PRO to treat Salmonella infections in poultry, its impact extends far beyond: This new technology holds the potential for transformative changes in phage therapy, not only advancing infection management in livestock farming through the enhancement of animal health and the assurance of food product safety, but also by opening the door for targeted preventive and therapeutic interventions in human medicine.