Phage cocktail shows promise against drug-resistant bacteria

Researchers have developed a new battle tactic to combat drug-resistant bacterial infections. Their strategy is to exploit collections of bacteriophages, viruses that naturally attack bacteria. In a new study, researchers at the University of Chicago's Pritzker School of Molecular Engineering (PME) and UChicago Medicine have shown that a mixture of these phages can successfully treat antibiotic-resistant Klebsiella pneumoniae infections in mice.

At the same time, however, the team's work showed how complex the interactions between phages and bacteria can be; The viruses predicted to be most effective in isolated culture dishes did not always work in animals. Additionally, both phages and bacteria can evolve over time – in some cases, phages evolved to be more efficient at killing bacteria, while in other cases, Klebsiella evolved resistance to the phages.

“We still believe that phages are an incredibly promising approach to treating drug-resistant bacteria like Klebsiella,” said Mark Mimee, assistant professor of molecular engineering and senior author of the new paper, published in Cell host and microbe. “But phages are like a living, ever-changing antibiotic, which gives them great complexity.”

Klebsiella pneumoniae are common bacteria that occur in the human intestine and cause little harm. However, if the bacteria get to other places in the body, such as open wounds, the lungs, the bloodstream, or the urinary tract, they can cause more serious infections. K. pneumoniae is commonly spread in hospitals, and drug-resistant strains are common.

“In my clinic, I see patients with recurrent urinary tract infections caused by Klebsiella,” says Urogynecologist Sandra Valaitis, MD, of UChicago Medicine, a co-author of the new paper. “Often these bacterial strains develop resistance to oral antibiotics, leaving patients with fewer options to cure the infection. We urgently need new ways to treat these bacteria.”

Phages have been considered natural enemies of bacteria for more than a century and have been studied for their potential to treat infections. However, phages tend to be very specific to a bacterial species, and it was difficult to predict these matches.

In the new research, Ella Rotman – a scientist in the Mimee Lab – examined wastewater to isolate phages that could effectively kill 27 different Klebsiella strains, including 14 newly isolated from patients at the University of Chicago. The team identified several dozen phages with the ability to kill at least some Klebsiella strains. The researchers then analyzed which genetic factors in the bacteria made them most susceptible to being killed or weakened by each of these phages.

Based on this analysis, Rotman and her colleagues developed a mixture of five phages, each targeting different components of the bacteria. In both culture dishes and mice, this phage cocktail increased the likelihood that antibiotic-resistant Klebsiella bacteria would be attacked by the immune system and, in some cases, made them more susceptible to antibiotic treatment. However, in other cases, the bacteria became more resistant to antibiotics after treatment.

“It's one of those things where biology often doesn't work the way you want it to,” says Mimee. “But it gives us the opportunity to study the detailed dynamics between the phages and the bacteria.”

By exposing the phage mixture to a series of isolated Klebsiella bacteria, the researchers gave the phage the opportunity to evolve. This improved the cocktail's ability to kill Klebsiella. In mice, the mixture effectively killed or weakened Klebsiella. The researchers observed coevolution between the bacteria and the phages in the mouse gut, where the Klebsiella evolved to evade the phage attack and the phages counterattacked to better infect the modified bacteria.

Mimee's lab group is continuing experiments to better understand how different pairs of phages and bacteria interact with each other and how the presence of other phages and bacteria that occur naturally in the human body influences this. At the same time, in collaboration with Valaitis, they are seeking approval from the Food and Drug Administration (FDA) for a small clinical trial testing the phage mixture in patients with urinary tract infections.

“This research is a positive step forward in trying to clarify the complexity of phages and bring them closer to the clinic,” says Mimee.