Neither Fully Alive Nor Dead: Synthetic Phages Could Speed Therapies Against Superbugs

Before antibiotics became widespread in the 1920s, bacteriophages—viruses that infect bacteria—were considered one of medicine’s best tools for fighting bacterial infections. A century later, the rise of antimicrobial‑resistant (AMR) bacteria has renewed interest in phage therapies, even as scientists work to overcome engineering and scalability challenges.

Researchers at New England Biolabs (NEB) and Yale University report a major advance in a study published in Proceedings of the National Academy of Sciences. Using a one‑pot High Complexity Golden Gate Assembly (HC‑GGA) approach, the team built a fully synthetic bacteriophage that targets the AMR pathogen Pseudomonas aeruginosa, an organism associated with hospital‑acquired infections ranging from skin and wound infections to severe pneumonia in vulnerable patients.

“Even in the best of cases, bacteriophage engineering has been extremely labor‑intensive,” said Andy Sikkema, co‑lead author from NEB. “This synthetic method offers technological leaps in simplicity, safety and speed, paving the way for biological discoveries and therapeutic development.”

Rather than isolating naturally occurring phages from environmental samples, the team assembled the P. aeruginosa phage from 28 synthetic DNA fragments. This modular design lets researchers fine‑tune phage behavior with point mutations and targeted DNA insertions or deletions (indels). The authors report that assembling the genome from shorter fragments also reduced toxicity in host cells used during assembly.

The HC‑GGA approach—essentially a streamlined, high‑complexity Golden Gate Assembly performed in a single pot—enables rapid construction of many variant genomes, which could accelerate screening for effective therapeutic candidates. NEB and Yale emphasize that this platform is designed to increase speed, flexibility, and safety relative to traditional, labor‑intensive phage engineering methods.

“My lab builds ‘weird hammers’ and then looks for the right nails,” said Greg Lohman, co‑author and Senior Principal Investigator at NEB. “In this case, the phage therapy community told us, ‘That’s exactly the hammer we’ve been waiting for.’”

NEB has prior phage experience: in December 2025 the group collaborated with Cornell University to develop phage‑based biosensors for detecting E. coli in drinking water. The new study builds on that expertise and demonstrates how synthetic assembly could be repurposed for therapeutic development against AMR pathogens.

While promising, the researchers and outside experts caution that this is an early step. Synthetic phages must still undergo extensive preclinical testing, evaluation for safety and efficacy, and regulatory review before they can become approved treatments. Manufacturing at clinical scale, avoiding unintended ecological effects, and ensuring consistent delivery to patients remain significant challenges.

The potential impact is urgent: a Lancet analysis estimates nearly 40 million deaths from AMR organisms between 2025 and 2050, and the World Health Organization reported that antibiotic resistance increased by more than 40% from 2019 to 2023. If synthetic‑assembly methods like HC‑GGA can be scaled and validated clinically, they could shorten development timelines and expand the toolbox against drug‑resistant bacteria.

Bottom line: The HC‑GGA synthetic phage represents a technical leap that may accelerate phage discovery and customization, but further testing and real‑world validation are required before it can be deployed as a standard therapy against AMR pathogens.