Bacteriophages — or phages, for short — are viruses that kill bacteria, and scientists have been studying them for decades as a possible solution to antibiotic-resistant infections. But phages are notoriously picky eaters — a phage that can eradicate one bacterial strain is often powerless against others, even if the bacteria are closely related. This means that a phage that works for one patient may be useless for the next.

Some phages, however, are exceptions — a rare few do have bigger appetites, and are capable of wiping out several strains of bacteria. Exactly what sets these broader-spectrum phages apart from their picky relatives has remained poorly understood, though — until now.

In a new study, published this week in the Proceedings of the National Academy of Sciences (PNAS), McMaster University researchers have described for the first time a trait shared by several broader-spectrum phages: particular forms of structural diversity in the fibres on their tails.

The new findings could make it easier to identify or design phage therapies that work against a broader range of bacteria, says principal investigator and professor emerita Lori Burrows.

“Phages use their tails to attach to the bacteria that they infect,” she explains. “By understanding why some phages can do this with only very specific bacterial strains and why others can be more promiscuous, we can focus on the types of phages that may have broader clinical utility.”

How Pseudomonas aeruginosa resists phage infection

To explore this broader-spectrum activity in phages, researchers in Burrows’ lab investigated how they interact with Pseudomonas aeruginosa, a common and often multidrug-resistant bacterium that causes dangerous hospital-acquired infections. Phages infect Pseudomonas by latching onto hair-like appendages on the bacterium’s surface, called pili.

These pili, which are made from molecular building blocks that Burrows describes as “lollipops,” vary in “flavour” across Pseudomonas strains. In fact, after analyzing genetic data from more than 1,300 unique P. aeruginosa strains, the research team found 53 distinct pili variants.

Because phages use these pili to recognize and attach to bacteria, even small differences can determine whether or not a phage can infect a particular strain.

“These variations were concentrated almost entirely on the part of the pili that phages interact with,” says Burrows, whose lab is based at the Michael G. DeGroote Institute for Infectious Disease Research. “This suggests that the bacteria have, over time, evolved different pili flavours to avoid their local phage populations.”

The team tested a panel of phages — including Cootes and Leland, phages Burrows’ lab named after roads near McMaster — against these different strains of P. aeruginosa, and observed two very distinct behaviours: Some phages were highly sensitive to even minor changes in pili, losing the ability to infect the bacteria, while others could tolerate large differences in pili, remaining infectious in situations where more selective phages could not.

“We wanted to understand why some phages can tolerate variation in the bacterial structures they attach to while others are much more sensitive,” says Ikram Qaderi, a PhD candidate in Burrows’ lab and first author on the new study.

Phage tail fibres reveal a marker of broader-spectrum activity

Comparing AI-generated models of the tail fibres these phages use to latch onto bacteria, researchers found a consistent difference between narrow-acting and broader-spectrum phages. Phages that were highly selective about which strains they could infect had tail fibres that were more similar to one another. The broader-acting phages, by contrast, had tail fibres that varied more at the point of contact with the pili, despite having an otherwise similar overall structure.

This pattern, Burrows says, held up not only across the phages tested in her lab, but also in dozens of similar phages identified in public databases, suggesting that the physical shape of a phage’s tail fibres may be a useful predictor of its activity.

Broader-spectrum phages could improve phage therapy

Being able to more easily identify broad-acting phages could help address a critical challenge in phage therapy, says Qaderi.

Because phages are typically so exquisitely narrow in what they target — unlike broad-spectrum antibiotics, which can indiscriminately knock out many different types of bacteria — doctors can’t just reach for a phage off the shelf. They must first identify the exact strain of bacteria behind the infection, and then identify and access the exact phage that preys on that strain.

“It can take weeks or longer for doctors to identify the right phage match for a patient’s particular bug,” Qaderi says. “For someone with a drug-resistant infection, that’s often time that they simply don’t have.”

These new findings build on a growing body of phage research from Burrows’ lab. Her team recently detailed how bacteria can evade phages and how phages can disarm bacteria — studies that, coupled with this recent work, all aim to help make phage therapy a more practical and scalable clinical option.

“Ideally, this work will make it easier for physicians to find and access phages that can infect a broader range of bacterial strains,” Qaderi says.

“Reducing the extreme precision required for effective phage therapy — and in turn the wait-times for patients — could make phages a more appealing and viable solution to antibiotic-resistant infections.”