PNAS Study Reveals Why Some Pseudomonas Phages Can Infect Far More Bacterial Strains
One of the biggest practical limitations of phage therapy is specificity. A bacteriophage capable of efficiently killing one bacterial strain may be completely ineffective against another strain of the same species, forcing clinicians to search through collections of viruses until they find a suitable match.
Researchers at McMaster University have now identified a structural feature that may help explain why a minority of phages escape this constraint. In a study published in the Proceedings of the National Academy of Sciences, the team reports that phages able to infect a broader range of Pseudomonas aeruginosa strains display greater structural diversity in the portions of their tail fibres that directly contact the bacterial surface.
The work was led by Ikram Qaderi, a PhD candidate in Lori Burrows’ laboratory at McMaster University’s Michael G. DeGroote Institute for Infectious Disease Research. Burrows, professor emerita at McMaster and principal investigator of the study, has spent years investigating the molecular interactions between P. aeruginosa and the phages that infect it.
The problem the researchers wanted to address is central to the future scalability of personalized phage therapy. Phages generally recognize highly specific receptors on bacterial surfaces. Even subtle changes in those receptors can prevent viral attachment and block infection altogether.
For a patient with a multidrug-resistant bacterial infection, this specificity can become a race against time. Identifying the pathogen is only the first step. Researchers may then need to screen that particular bacterial isolate against numerous candidate phages before finding one capable of productive infection.
According to Qaderi, obtaining the correct match can sometimes require weeks or longer. For critically ill patients with resistant infections, such delays can severely limit the practical utility of personalized treatment.
The McMaster team therefore approached the problem from the opposite direction: rather than asking why most phages have narrow host ranges, they investigated the unusual phages capable of infecting multiple bacterial strains.
Their model organism was Pseudomonas aeruginosa, an opportunistic pathogen responsible for serious infections including hospital-acquired and chronic respiratory infections. It is particularly important in antimicrobial resistance research because clinical strains can develop resistance to multiple antibiotic classes and possess numerous mechanisms for resisting both antibiotics and bacteriophages.
Many phages targeting P. aeruginosa initiate infection through type IV pili, thin filamentous structures extending from the bacterial surface. These pili participate in functions such as motility, adherence and biofilm formation, but they can also serve as receptors exploited by bacteriophages.
For a phage, recognition of the pilus is one of the earliest steps determining whether infection will succeed. Viral tail fibres or related receptor-binding structures interact with the bacterial pilus, enabling the phage to attach and begin the infection process.
Burrows compares the building blocks of these pili to molecular “lollipops.” Importantly, those lollipops do not all look the same.
The McMaster researchers analysed genetic data from more than 1,300 distinct P. aeruginosa strains and identified 53 different pilus variants. Much of that diversity was concentrated specifically within the regions of the pilus exposed to phage interaction.
That distribution is unlikely to be biologically trivial. Phages exert strong evolutionary pressure on bacterial populations, and changing the surface structures recognized by viruses provides bacteria with a straightforward means of escaping infection.
The researchers therefore propose that the diversity observed among Pseudomonas pili reflects, at least partly, the long-running evolutionary arms race between bacteria and the phages that prey on them.
A receptor mutation can prevent one phage from binding. The virus population, in turn, faces pressure to evolve new receptor-binding structures capable of recognizing the altered bacterial surface. Repeated over evolutionary time, that competition can generate extraordinary diversity on both sides.
The team tested multiple phages against P. aeruginosa strains carrying different pilus variants. These included phages named Cootes and Leland after roads near McMaster University.
Two contrasting infection strategies became apparent.
Some phages were extremely sensitive to variation in the bacterial pilus. Even relatively minor changes were sufficient to prevent productive infection. These viruses therefore displayed the narrow host specificity commonly associated with bacteriophages.
Other phages behaved very differently. They remained capable of infection despite substantial variation in the pili of different bacterial strains.
The central question became why.
Researchers compared AI-generated structural models of the tail fibres used by these phages to interact with bacterial pili. Narrow-host-range phages displayed tail fibres that were comparatively similar to one another in the regions associated with receptor recognition.
The broader-host-range phages showed a different pattern. Their overall tail-fibre architecture remained related, but the region making contact with the bacterial pilus displayed greater structural variation.
This localized diversity appears to provide broader phages with more flexibility in recognizing different versions of the same bacterial receptor.
The observation is important because it transforms broad host range from a largely empirical property into something that may eventually be predicted from molecular structure.
Today, finding a broadly active therapeutic phage usually involves screening. Researchers expose multiple bacterial isolates to many phages and experimentally determine which combinations permit infection.
If characteristic structural signatures reliably correlate with broad host range, researchers could instead prioritize phages carrying those features before conducting extensive experimental screening.
The McMaster team tested whether the pattern extended beyond the small set of phages characterized experimentally. Similar structural relationships were identified among dozens of related phages retrieved from public databases, strengthening the possibility that tail-fibre architecture may provide a more general indicator of host-range behaviour.
The result does not mean that tail-fibre diversity alone determines whether a phage has broad therapeutic activity. Successful infection involves multiple stages after receptor recognition, including genome entry, evasion of bacterial antiviral defences, viral replication, assembly and release.
A phage that attaches successfully to many bacterial strains can still fail if one of those strains possesses an intracellular defence system capable of stopping infection.
Host range is therefore the product of several molecular barriers. What the McMaster study provides is a clearer explanation of one particularly important barrier: recognition of the bacterial surface.
That distinction could be useful both for discovering natural phages and for engineering new ones.
If scientists can identify the structural features that allow some tail fibres to tolerate receptor variation, those properties could potentially become design principles for phage engineering. Instead of searching exclusively for naturally broad phages, researchers might eventually modify receptor-binding regions to expand the number of bacterial variants recognized by an existing therapeutic phage.
This possibility fits within a broader shift occurring in phage biotechnology. Phage discovery historically depended on isolating viruses from environmental samples and screening them against bacteria of interest. Increasingly, structural biology, large-scale sequencing, machine learning and synthetic biology are being used to understand why particular phages behave as they do and whether those behaviours can be redesigned.
For P. aeruginosa, such strategies could be particularly useful because the organism is exceptionally diverse. A phage preparation active against one clinical isolate cannot be assumed to work against another simply because both are classified as P. aeruginosa.
Broadly active phages could reduce that dependence on exact matching.
Instead of maintaining a therapeutic collection in which every bacterial strain requires an individual phage, a smaller number of carefully selected broad-host-range viruses might collectively cover a substantially larger fraction of clinical isolates.
That could reduce screening time and simplify the development of standardized phage cocktails.
It could also make emergency use more practical. Personalized phage therapy frequently depends on receiving the patient’s isolate, performing susceptibility testing and obtaining an appropriate phage from a laboratory or phage bank. Every additional step adds time.
A collection enriched for phages already predicted to tolerate common receptor variants could make the first round of screening substantially more efficient.
There is nevertheless an important therapeutic trade-off.
One advantage of bacteriophages over broad-spectrum antibiotics is precisely their narrow specificity. Antibiotics can eliminate beneficial microorganisms along with pathogens, whereas a highly specific phage may remove a bacterial target while leaving most of the surrounding microbiome intact.
The objective therefore may not simply be to engineer phages with the broadest possible host range.
A more useful goal could be controlled breadth: phages broad enough to infect many clinically important variants of one pathogen while remaining restricted enough to avoid unrelated bacterial species.
The McMaster findings provide a molecular framework for thinking about that balance.
They also demonstrate how deeply bacterial and phage evolution are interconnected. The 53 pilus variants identified across more than 1,300 P. aeruginosa strains illustrate the extraordinary diversity generated at the interface between a virus and its receptor. Bacteria modify the structures targeted by phages; phages diversify the structures used to recognize them.
Broad-host-range phages appear to represent one evolutionary answer to that problem.
Rather than depending on an extremely rigid interaction with one version of the receptor, their receptor-binding machinery appears capable of accommodating greater structural variation.
For phage therapy, understanding that flexibility could ultimately be more important than simply cataloguing another broad-spectrum virus.
It provides a clue to what researchers should look for.
The immediate result is therefore not a new ready-to-use treatment. The study instead identifies a molecular feature that could help researchers recognize phages with greater therapeutic coverage and potentially guide future engineering of receptor-binding proteins.
Qaderi and Burrows ultimately hope this information can reduce one of the major logistical obstacles facing phage therapy: the extreme precision currently required to match a virus with a patient's bacterial strain.
If structural properties of phage tail fibres can be developed into reliable predictors of host range, screening could become more targeted, phage libraries could be organized more intelligently and therapeutic cocktails could be designed around viruses with complementary coverage.
For a field attempting to move from highly individualized rescue treatments toward scalable antimicrobial products, that seemingly small improvement could have substantial consequences.
The study also reinforces a broader lesson emerging across modern phage research: knowing that a virus kills a bacterium is no longer enough.
Researchers increasingly want to understand why it kills that bacterium, which molecular interactions determine its host range, how bacteria escape infection and which viral structures can be modified to overcome those barriers.
By connecting variation in Pseudomonas pili with corresponding diversity in phage tail fibres, the McMaster team has provided another piece of that mechanistic map — and potentially a way to identify the phages most likely to be useful before precious clinical time is spent searching for them.
Sources :
McMaster University Faculty of Health Sciences — Blake Dillon, McMaster researchers uncover what could make some bacteria-killing viruses more effective than others, September 22, 2026.
https://healthsci.mcmaster.ca/mcmaster-researchers-uncover-what-could-make-some-bacteria-killing-viruses-more-effective-than-others/
Qaderi and colleagues. Proceedings of the National Academy of Sciences (2026).
https://doi.org/10.1073/pnas.2626959123
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