Natural and engineered bacteriophages against multidrug-resistant ESKAPE pathogens: current landscape and clinical translation

The worldwide emergence of antimicrobial resistance and the need for non-conventional alternatives to conventional antibiotics have been increased by multidrug-resistant ESKAPE pathogens, which cause the majority of nosocomial infections and are starting to develop resistance to even the most potent drugs. Engineered bacteriophages are promising precision antimicrobials because of their ability to selectively infect and lyse bacterial hosts, multiply at infection sites, and co-evolve with bacterial populations to overcome resistance. Advances in synthetic biology, such as tail fiber modification, depolymerase and endolysin enhancement, genome editing using the clustered regularly interspaced short palindromic repeats (CRISPR), and computationally designed phage cocktails, have opened new possibilities for therapeutics that were hindered by the limitations of natural phages. These engineering strategies expand host range, enhance biofilm penetration, and target resistance genes. In spite of promising evidence in preclinical models, the use of engineered phages in routine clinical practice remains difficult. Specific key challenges include unclear regulations, lack of good manufacturing practice (GMP)grade production, variable pharmacokinetics and limited clinical trial data. This review critically examines engineering approaches to improve phage activity against ESKAPE pathogens, identifies the scientific and regulatory barriers limiting clinical use, and outlines the key steps needed for wider adoption.