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Joshua Williams, Ioannis P Nezis, Antonia P Sagona

The rising incidence of antimicrobial resistance (AMR) in bacterial infections has strongly necessitated the development and deployment of alternative therapeutics. Bacteriophages (phages) are one such alternative, discovered in the early twentieth century. While a key tool in landmark molecular biology studies throughout the twentieth century, their popularity as an antimicrobial in clinical contexts was largely overshadowed by the development and use of antibiotics. The global threat of AMR has since reignited interest in utilizing phages as therapeutics. A key advantage of phages is their genetic tractability, allowing for the generation of a cornucopia of derivatives armed with numerous exogenous functions depending on the end use. A nascent yet growing interest in this field is the arming of phages for direct and selective human tissue entry to eradicate intracellular bacterial infections, where many bacterial species exert their pathogenesis. Engineering phages in such a way also opens opportunities to study the complex, multilayered cellular mechanisms behind phage–eukaryote interactions. In this review, we discuss the progress of phage genetic engineering with an emphasis on phage–eukaryote interactions and how knowledge of the underlying molecular mechanisms may serve further development of this prospective enhancement of engineered phages.