| Summary: | ABSTRACT The rapid global spread of antibiotic‐resistant bacteria presents a growing public health crisis, threatening the efficacy of existing antimicrobial treatments. As traditional antibiotics become increasingly ineffective, alternative therapies such as bacteriophages and endolysins have gained renewed scientific and clinical interest. These biological agents, naturally derived from bacteriophage life cycles, exhibit potent and selective antibacterial activity, especially against multidrug‐resistant pathogens. Despite decades of research, the clinical translation of phage and endolysin therapies remains limited due to regulatory, delivery, and stability challenges. This review provides a comprehensive overview of the mechanisms, advantages, and limitations of both bacteriophages and endolysins, including their structure, mode of action, and interaction with bacterial hosts. Particular attention is given to combination therapies, where synergistic effects have been observed–especially in biofilm‐associated infections. We also explore the latest findings from preclinical studies, clinical trials, and compassionate‐use cases, with an emphasis on genetically engineered and synthetic variants that enhance therapeutic potential. Furthermore, we discuss manufacturing challenges, regulatory barriers, and future directions such as personalized phage therapy and engineered endolysins. By synthesizing current knowledge, this review highlights the academic and translational significance of phage and endolysin‐based approaches in combating antibiotic‐resistant infections.
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