A stubborn bacterial threat has exposed a key weakness in phage therapy
Researchers from A*STAR Infectious Diseases Labs, Nanyang Technological University, the National University of Singapore, and collaborators say they have uncovered how Mycobacterium abscessus can evade bacteriophage therapy and have demonstrated a two-pronged strategy to overcome that resistance. Published in the Proceedings of the National Academy of Sciences, the work offers what the team describes as actionable design principles for building more durable phage cocktails against drug-resistant infections.
The findings matter because M. abscessus is a difficult pathogen with growing public health significance. It can cause serious lung infections and is intrinsically resistant to many antibiotics, making treatment challenging. In a world where antimicrobial resistance is steadily eroding the usefulness of conventional drugs, alternatives such as phage therapy have drawn increasing interest. Phages are viruses that infect bacteria, and they can sometimes be used to target pathogens that have become difficult to manage with antibiotics alone.
But phage therapy has its own problem: bacteria evolve. The new study focuses squarely on that obstacle by asking not simply whether phages can work, but how bacterial escape happens and how treatment design can limit it.
How the bacterium changes to survive
The researchers found that so-called smooth strains of M. abscessus, which the report notes are more commonly observed in Asia, can respond to phage pressure by switching to a rough form in both laboratory and preclinical models. That transition was linked to mutations in genes involved in producing glycopeptidolipids, molecules that shape the bacterium’s outer surface.
This matters because surface structure influences how phages recognize and attack bacterial cells. By changing that surface, the bacterium can effectively alter the target phages are trying to hit. The team also found that resistance did not always require a smooth-to-rough switch. In some cases, bacteria remained in place phenotypically but still escaped phage attack through mutations in other surface-related genes. Taken together, the results suggest that M. abscessus has multiple routes to evade treatment.
That multiplicity is exactly what makes durable therapy so difficult. If a pathogen has only one predictable escape path, it may be possible to block it with a well-chosen combination. If it has several, treatment must be designed with evolutionary flexibility in mind.
