Abstract

The inevitable expansion of Antimicrobial Resistance (AMR) poses a serious danger to global health, leaving many frontline antibiotics increasingly ineffective and driving the pressure for new therapeutic options. Among the most promising developing techniques are bacteriophage therapy and phage derived endolysins, which offer targeted, powerful, and evolutionarily adaptable strategies for treating Multidrug Resistant (MDR) bacterial infections. Traditional phage therapy, however, is hindered by significant limitations, including narrow host specificity, rapid emergence of phage resistant variants, inconsistent clinical outcomes, challenges in large-scale manufacturing, and regulatory barriers that impede standardization and widespread implementation.
This review presents a comprehensive examination of recent improvements in precision phage therapy, a promising antibacterial technique that uses technological innovations to overcome persistent limits of traditional treatments. Large-scale phage libraries and coordinated biobanking systems have made it possible to match phages to pathogens quickly and accurately, and genetic engineering and synthetic biology have increased the variety of phage hosts, improved safety profiles and added programmable diagnostic features. Rational design of phage mixtures further broadens antibacterial spectrum and mitigates resistance emergence. In parallel, new research highlights the role of phage-antibiotic synergy in boosting therapeutic efficacy and regulating mutant selection, although this synergy is contextdependent and antagonistic or non-beneficial interactions can occur depending on the phage, antibiotic, dose and bacterial strain involved. This review also emphasizes developments in the engineering of endolysins which display quick and powerful bacteriolytic activity, including against biofilm associated and Gram-negative pathogens when appropriately engineered. Preclinical studies consistently reveal large decreases in bacterial burden, improved survival outcomes and positive safety across multiple infection scenarios. Early phase clinical trials support the safety and acceptability of phage-based therapies, however robust efficacy data remain sparse. Challenges such as immunogenicity and short in vivo survival exist, however modified lytic enzymes continue to show substantial potential. All things considered, these advancements make endolysin based modalities and precision phage therapy attractive options for next-generation treatments amid growing antibiotic resistance.