Phage Therapy and Phage-Derived Lytic Proteins in the One Health Era: Mechanisms, Challenges and Emerging Innovations

Antimicrobial resistance is a critical global health threat, as conventional antibiotics are increasingly ineffective against multidrug-resistant (MDR) pathogens, particularly ESKAPE organisms. In response, bacteriophages and their derived lytic proteins, including endolysins, holins, and spanins, have emerged as promising therapeutic alternatives. This review examines the comparative therapeutic potential of phages and phage-derived lytic proteins as complementary antibacterial strategies within a One-Health framework, which remains underdeveloped. We explore phage biology, including both lytic and lysogenic cycles, as a mechanistic foundation for understanding their role in addressing the growing threat of antimicrobial resistance. Additionally, we detail bacterial defense mechanisms, such as restriction modification systems, CRISPR-Cas systems, and spontaneous mutations that confer phage resistance. Lytic proteins demonstrate efficacy in treating systemic infections, disrupting biofilm, and targeting resistant pathogens across humans, livestock, and aquaculture. Although phage therapy is a promising antibacterial alternative, it still faces several constraints, including a narrow host range, immune clearance, complex pharmacokinetics, and the inability of exogenous lytic proteins to cross the outer membranes of Gram-negative bacteria. This review highlights emerging solutions to these challenges, including the use of artificial intelligence (AI) for phage and lysin discovery, machine learning models for predicting effective phage combinations, and the engineering of phage lytic proteins to broaden antimicrobial spectra. It also discusses combination strategies that pair whole phages with their derived proteins to exploit synergistic antibacterial effects and counter the emergence of resistance, as well as advanced delivery systems designed to protect phage integrity and enhance activity in hostile physiological environments.