• Scientists have proposed that phages — viruses that replicate inside bacteria — could help stem the rising tide of antibiotic resistance.
• However, the discovery that bacteria growing in culture flasks in the laboratory evolve rapid genetic resistance to these viruses has hindered earlier attempts to develop phage therapies.
• A new study suggests that this is less likely to occur in parts of the body where susceptible bacteria remain in tight spaces, such as capillaries.
• Researchers believe that a cocktail of antibiotics and phages may one day provide effective treatments against antibiotic resistant bacteria.

According to the World Health Organization (WHO), antibiotic-resistant bacteria pose one of the greatest threats to global health, food security, and development.

In recent decades, an increasing number of bacterial infections, including tuberculosis, pneumonia, and salmonellosis — a type of food poisoning, have become resistant to antibiotic drugs.

And as antibiotics become less effective at killing bacteria, this inevitably leads to longer hospital stays, higher medical costs, and increased mortality.

”Antibiotic resistance is here, and it is threatening to undermine not just our ability to treat infections themselves, but also threatens the ability to provide other types of treatment,” said Dr. David Hyun, of the Pew Charitable Trusts’ antibiotic resistance project, speaking on the First Opinion podcast earlier this year.

“Even simple surgeries could become dangerous procedures,” he added.

He said current antibiotics are being overused, and their effectiveness is diminishing rapidly.

At the same time, the pipeline of new drugs has dried up because there is little financial incentive for pharmaceutical companies to develop new ones.

This is partly because, unlike drugs, such as statins, most people only take antibiotics for a matter of days, he said. In addition, any new drug would be held in reserve by doctors as a “treatment of last resort” to preserve its efficacy.

Viruses that prey on bacteria

One possible solution is for healthcare professionals to enlist the help of bacteriophages, or “phages,” which invade bacteria and hijack their cellular machinery to make copies of themselves. In the process, this kills the bacteria.

Bacteriophages are the most abundant biological entities on the planet. By keeping bacteria in check, they help maintain a healthy balance between microorganisms.

The French microbiologist Félix d’Hérelle discovered bacteriophages more than 100 years ago and came up with the idea that they could treat bacterial infections. In 1919, he used a cocktail of phages to cure four patients of dysentery.

With the development of highly effective antibiotic drugs in the following decades, phage therapy fell out of favor. But there has been a revival of interest in recent years as a possible way to address the growing threat of antibiotic resistance.

One of the challenges for researchers has been to recreate how phages and their bacterial hosts behave in the human body in the laboratory.

When scientists grow bacteria and phages together in a flask, the bacteria evolve rapid genetic resistance to the viruses.

However, a new study has found that in an environment that more closely resembles the nooks and crannies of the human body, such as blood capillaries or the alveoli — or air sacs — in the lungs, bacteria do not develop genetic resistance to phages.

This suggests that even if bacteria survive in such places, phages can prevent them from reaching dangerously high population densities.

The scientists recently published their research in PLOS Biology.

“Antibiotic resistance could prove a greater killer than COVID-19 if we don’t find new ways to fight infection,” says senior author Stefano Pagliara, Ph.D., a Living Systems Institute biophysicist at the University of Exeter in the United Kingdom.

“Phage therapy shows great promise as being part of the picture, and our research has helped overcome some of the obstacles so far by mimicking how bacteria behave in small vessels in our bodies,” he adds.

Tight spaces

The researchers used a technology called microfluidics to mimic “microenvironments” that restrict access and movement.

Microfluidics allows microbiologists to introduce a single bacterium into a channel about a thousandth of a millimeter in diameter and then control and monitor its environment.

The narrow space prevents the cell from moving around freely or dividing rapidly to form a colony.

The researchers compared the effect of a phage called T4 on Escherichia coli bacteria either in an open environment or confined to these narrow channels.

They discovered that the bacterial population grew rapidly in the open environment, then crashed after the scientists introduced the phages.

However, the population later rebounded to its former level, suggesting that the bacteria had developed genetic resistance to the phages.

In contrast, while bacteria in the confined environment grew much more slowly, the phages did not eliminate them.

The researchers discovered that these bacteria survived not by evolving genetic resistance, but by reducing or “downregulating” the number of receptors in their cell walls that the virus uses to invade them.

As a result, the phages successfully controlled the population of bacteria without wiping them out or promoting genetic resistance.

“Our research indicates that if we can find new ways of promoting the production of phage receptors in bacteria, we could improve the prospects of phage therapy as a viable alternative to antibiotics,” says co-author Edze Westra, Ph.D., from the University of Exeter.

“The idea of phage downregulating receptors to evade phage resistance, and the idea of pockets of susceptible and resistant clones, are both established mechanisms,” said Jeremy Barr, Ph.D., who heads the Bacteriophage Biology Research Group at Monash University in Melbourne, Australia.

“This work takes both concepts together and shows using a microfluidics setup that downregulation of receptors can couple with a structured environment to provide pockets of surviving bacteria,” he told MNT.

The future of phage therapy

Dr. Pagliara believes the best strategy to fight bacterial infections without fostering genetically resistant strains may be to combine phages and antibiotics in a single treatment.

“[T]his is something that we and others are working on,” he said. “My opinion is that phage cocktails, phage-antibiotic combination therapies, [or both] are the future.”

However, the authors concede that their experimental setup is not an exact model of the complexities of the human body. That said, they write that researchers could use it to complement standard lab methods for studying how phages affect the survival of disease-causing bacteria.

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