Harnessing ‘phage training’ to bolster the therapeutic potential of bacteriophages

Bacteriophages (phages) are viruses that selectively prey on bacteria. Their use in treating antimicrobial-resistant bacterial infections is steadily increasing due to the need for alternative therapies. The application of phage therapy is not without its challenges, including difficulties associated with isolating phages against a target strain, the limited infectivity of a phage, the cost and complexity of producing well-characterised phage stocks, and the emergence of phage resistance. The directed adaptation of phage to a specific bacterial target, also known as 'phage training', leverages the natural evolutionary capacity of phages and can be used to bolster their bacterial killing abilities. Phage training dates back almost as far as phage therapy itself, being used to expand the therapeutic use of phages. Numerous reports showcase the success and benefits of phage training in vitro and its potential to operate effectively within the framework of phage therapy. However, the time needed to train a given phage, followed by genotypic and phenotypic characterisation of both pre- and post-trained phages, is a major limitation. Here, we explore oversights of the phage training process and propose some considerations and solutions to help drive the field forward to enable its feasible integration into phage therapy.