Viruses that selectively target and kill bacteria — also known as bacteriophages or simply phages — infect bacteria but leave human cells alone. Once they attach to a bacterial cell, they inject their genetic material, hijack the cell's machinery and force it to produce new phages until the bacterium bursts.

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The problem is that bacteria can evolve defences against phages, just as they evolve resistance to antibiotics.

The new research suggests that phages have their own evolutionary countermeasure.

Some of the viruses living in the human gut can rapidly generate genetic variations among their offspring, increasing the chances that at least some will survive when bacteria fight back, according to the study, published Thursday in Nature Microbiology.

The finding could offer a new route in the search for alternatives to antibiotics, as drug-resistant infections become harder to treat.

Researchers at Michigan State University have identified previously underappreciated regions of bacteriophage genomes that act as genetic “hotspots”, allowing the viruses to repeatedly alter key genes as they replicate.

This suggests these regions help phages hedge their evolutionary bets against bacterial defences. Rather than producing a population of genetically identical viruses, they generate a diverse collection of offspring with different characteristics — increasing the odds that some can continue infecting and killing their bacterial hosts.

“This changes our understanding of how phages evolve,” said co-author Chris Waters, a faculty member in Michigan State University’s Ecology, Evolution, and Behavior program. “Instead of hijacking their hosts to mass produce exact copies of themselves, they are actually using these mutation hotspots to make a zoo,” he said, adding that phages are “essentially hedging their bets.”

A genetic escape route

The researchers studied bacteriophage T2, which infects E. coli, after examining a bacterial defence system that can recognise and destroy invading phage DNA.

The team transferred the defence system into E. coli in the laboratory and exposed the bacteria to phages.

The protection did not last.

Within hours, the phages began overcoming the bacterial defences.

“Within a few hours, the phages always started to win,” Waters said. “We couldn’t understand why,” he added.

When researchers sequenced the resistant viruses, they found repeated mutations in a gene called agt, particularly in a stretch of repetitive DNA. “When I saw the data, I thought, oh my gosh,” Waters said.

That sequence turned out to be what scientists call a contingency locus — a highly mutable region where the DNA-copying machinery can slip when replicating repeated sequences.

The result is a reversible frameshift mutation that can change how the gene's instructions are read.

Some phages gain an extra repeat; others lose one. The result is a population containing different versions of the virus, potentially with different abilities to evade bacterial defences.

The researchers found that these repetitive regions accumulated mutations thousands of times faster than the rest of the phage genome.

And the mechanism is not confined to a single virus.

Using experimental evolution and genome sequencing, the researchers found similar contingency loci in E. coli phage T4. They also found that simple sequence repeats were widespread across diverse E. coli phages, although their abundance varied between genes with different functions.

Could it help treat superbugs?

The research comes as scientists and policymakers look for alternatives to antibiotics.

Phage therapy is not new. Phages were used therapeutically as early as the 1920s to treat bacterial infections, but interest in the approach declined after antibiotics such as penicillin became widely available.

Now the rise of antimicrobial resistance has revived interest.

The appeal is partly down to specificity. Whereas many antibiotics can kill beneficial bacteria alongside the pathogen they target, individual phages can be highly selective for particular bacterial species or strains.

But that specificity is also a weakness: bacteria can evolve resistance to a phage, potentially rendering a treatment ineffective.

The Michigan State findings raise the possibility that scientists could eventually exploit the viruses' own evolutionary strategies to make phage treatments more resilient.

“If we can harness these kinds of evolutionary tricks, we might be able to make more effective phage therapies in response to the antibiotic resistance crisis,” Waters said.

“We’re never going to be able to completely get rid of resistance,” he added. “But if we can better understand how bacteria protect themselves from phage infection and how phages fight back, we might be able to minimize it.”