The continuously increasing antimicrobial resistance (AMR) presents a global threat to human as well as animal health, necessitating the development of alternative therapeutic approaches beyond conventional antibiotics. This chapter highlights the potential of bacteriophages (or just phages) and orally administered β-lactamase enzymes as alternative and synergistic agents to mitigate AMR and maintain gut homeostasis. Phages, as natural predators of bacteria, offer targeted removal of pathogenic bacteria without affecting the commensal gut microflora. While β-lactamases are natural enzymes that degrade β-lactam antibiotics, they can be utilised to preserve the commensal gut microflora from the undesired damage caused by antibiotic use. Besides various advantages of the phage therapy, such as effect limited to infection site, easy isolation, mode of action different from antibiotic resistance, there exists few challenges in the implementation of phage therapy for clinical usage, which are difficulty in obtaining regulatory approval for mixed strains, adverse immune response, inability to penetrate biofilms, transfer of antibiotic-resistance genes and other virulence factors, lack of clear official guidelines for production and utilisation etc. A few of the limitations can be overcome by developing genetically engineered phages and endolysins. In conclusion, the phages have become the biggest hopes for treatment of resistant infections in future, although to achieve commercial application more research and development is required. The findings underscore the promise of phage-therapy as a precision-based approach to control AMR in the gastrointestinal ecosystem and highlight its potential integration into future antimicrobial stewardship programs.

Keywords: Antibiotic; Gut microbiota (GM); Antimicrobial resistance (AMR), Phage therapy, Endolysins, β-lactamases