Bacteria-Killing Viruses Can Help Us Take Down Superbugs

Fighting fire with fire, scientists are harnessing the adaptability of helpful microbes to challenge the adaptability of deadly microbes. What are we talking about? Hunting with phages — viruses that attack and kill bacteria.

Bacteriophages are small, skeletal viruses that attack bacteria to hijack their machinery to make more bacteriophages, or "phages." It's a microbe-eat-microbe world, after all.

In the early 1900s, a French-Canadian scientist named Félix d' Hérelle first identified bacteriophages while working at the Pasteur Institute in France. D'Hérelle studied and experimented with the microbes and was the first to suggest what was then a preposterous notion — "phage therapy" — intentionally inoculating someone with viruses to fight off bacterial infections.

For example, phages, which already naturally attack bacteria for a living, could be used as natural antimicrobials. D'Hérelle and other scientists identified phages that were able to kill dangerous pathogens of the time, including Salmonella typhi, Escherichia coli, and Vibro cholera.

D'Hérelle's phage therapy theories spread around the globe to acclaim and significant success. For reasons of politics or possibly the introduction of penicillin, d'Hérelle's ideas fell out of favor with academic physicians, who later pilloried his ideas and methods as lacking proper knowledge or rigor.

Diminished in the West, phage therapy was never fully discarded in Europe or the former Soviet Union. Today, as medical science is pressed to find antibiotic alternatives, Western science is taking another look at phage therapy.

Using Bacteriophages to Battle Superbugs

In research published in the journal Scientific Reports, scientists at Baylor College of Medicine revisited the ideas of d'Hérelle. In a press release, co-author Robert Ramig, professor of molecular virology and microbiology at Baylor said, "The driving force behind this project was to find phages that would kill 12 strains of antibiotic-resistant bacteria that were isolated from patients."

Just as d'Hérelle had done almost a century ago, the research team isolated phages from specimens gathered primarily from dogs and birds, suspected reservoirs of multidrug-resistant pathogens. As reservoirs, the team thought they might also find phages specialized to kill those bacteria in bird and dog feces — and they were right.

Although the team was unable to find one phage that would kill all 12 strains of bacteria, scientists were able to combine two and three different types of phages that successfully killed the targeted strains. Specifically, the group focused on phages that could kill extraintestinal pathogenic E. coli, known as ExPEC, a group of pathogens that cause meningitis, urinary tract infections, sepsis, and other diseases.

Viral bacteriophages seen by cryo-EM imaging with tail contracted

Attacking Sepsis with Phages

Sepsis is an often fatal infection that occurs when a pathogen attacks and the body cannot overcome. In a stormy immune response, the body mounts a no-win attack on the invader, leading to loss of blood pressure, organ failure, and ultimately death.

As study authors report, approximately 750,000 cases of sepsis occur each year, accounting for 6% of all US deaths between 1999 and 2014 — a full quarter of these fatalities are from urinary or gastrointestinal tract infections caused by drug-resistant bacteria.

To test phage therapy during sepsis, researchers infected mice with a virulent, drug-resistant strain of ExPEC. To mimic the effect of immune suppression experienced by chronically ill humans, the mice received chemotherapy. The immune suppression let the drug-resistant pathogens in the mice to expand into their organs, creating a mouse version of a deadly sepsis infection.

When treated with a cocktail of phages isolated to target ExPEC strains, the numbers of circulating bacteria dropped below levels needed to mount a lethal attack on the mouse immune system. Later analysis revealed the phages also circulated to the major organs, scavenging ExPEC throughout.

Anthony Maresso, associate professor of molecular virology and microbiology at Baylor, said:

When the phages are delivered into the animals, their efficacy in reducing the levels of bacteria and improving health is dramatic. What is remarkable is that these 'drugs' were discovered, isolated, identified and tested in a matter of weeks, and for less money than most of us probably spend in a month on groceries.

Phage cocktails offer a possibly promising weapon against deadly pathogens, but they are not cure-alls. Points to consider about phage therapy include:

• Some bacteria are resistant to phage infection.
• Phages do not attack human cells, but the human immune system recognizes them as invaders and often acts to remove them from the body.
• Researchers must carefully select for non-virulent but effective phages.
• Phages are alive; they can evolve during the copying process inside bacteria. If they evolve on the fly, they may no longer work the way researchers want them to, meaning they're inconsistent as pharmaceuticals and require specialized adaptation and use. That also means they can adapt to changing bacteria.
• Phages are potentially inexpensive to develop and natural. They offer an entirely different antibacterial process and can scale up their numbers on the battle ground inside the body, making them "adaptive drugs."

Study authors say hunting down bacteria with phages could prove effective against drug-resistant bacteria and harness the adaptability of phages to fight the adaptability of viruses.

"There are many ways to kill bacteria, but I know of no other way that has the potential to evolve in real time like phages do," Maresso said. "And it's the best 'green' medicine — it's natural, safe thus far, relatively cheap and can be harnessed with the technical skills of a college biology major."

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Cover image via Bacter/Wikimedia Commons