Bacteriophages have been used to treat bacterial infections for more than a century, but their therapeutic potential has remained largely untapped in modern medicine. As antibiotic resistance continues growing as a global threat, a new study published details a technological breakthrough that could accelerate bacteriophage-based drug development.

Researchers from New England Biolabs (NEB®) and Yale University have developed the first fully synthetic bacteriophage engineering system for Pseudomonas aeruginosa, a highly antibiotic-resistant pathogen. The research introduces a faster, safer and more versatile approach to engineering bacteriophages using digital sequence data rather than relying on naturally isolated viruses.

Building phages from sequence data

The new system is based on NEB’s High-Complexity Golden Gate Assembly (HC-GGA) platform, which enables the assembly of entire bacteriophage genomes outside the cell from short synthetic DNA fragments. In the study, the team constructed a P. aeruginosa phage from 28 synthetic fragments and programmed new behaviours through point mutations, insertions and deletions. 

These genetic modifications included swapping tail fibre genes to alter the phage’s bacterial host range, as well as inserting fluorescent reporter genes to allow real-time visualisation of infection. By assembling phages directly from sequence data, the researchers could incorporate all intended genetic changes in a single step.  

“Even in the best of cases, bacteriophage engineering has been extremely labour-intensive. Researchers spent entire careers developing processes to engineer specific model bacteriophages in host bacteria,” said Andy Sikkema, co-first author and research scientist at NEB. “This synthetic method offers technological leaps in simplicity, safety and speed, paving the way for biological discoveries and therapeutic development.”