Researchers have a new battle tactic to fight drug-resistant bacterial infections. Their strategy involves using collections of bacteriophages, viruses that naturally attack bacteria. In a new study, researchers at the University of Chicago 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 revealed just 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. Moreover, both phages and bacteria can evolve over time – in some cases, phages evolved to be more efficient in killing bacteria while in other cases, Klebsiella evolved resistance to the phages.
"We still think phages are an incredibly promising approach to treating drug-resistant bacteria such as Klebsiella," said Mark Mimee, assistant professor of molecular engineering and senior author of the new work, published in Cell Host & Microbe. "But phages are like a living, constantly changing antibiotic which gives them a lot of complexity."
Klebsiella pneumoniae are common bacteria found in people's intestines where they cause little harm. However, when the bacteria escape to other body sites, such as open wounds, the lungs, the bloodstream, or the urinary tract, they can cause more severe infections. K. pneumoniae are often spread within hospital settings, and drug-resistant strains have become 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 work. "Often these bacterial strains develop resistance to oral antibiotics, leaving patients with fewer options to clear the infection. We urgently need new ways of treating these bacteria."
Phages, for more than a century, have been known as a natural enemy of bacteria and studied for their potential to treat infections. However, phages are usually very specific for one type of bacteria and predicting these matches has been difficult.
In the new research, Ella Rotman – a scientist in the Mimee Lab – screened wastewater to isolate phages that could effectively kill 27 different Klebsiella strains, including 14 that were newly isolated from University of Chicago patients. The team identified several dozen phages with the capability of killing at least some Klebsiella strains, Then, the researchers analyzed what genetic factors in the bacteria made them most prone to being killed or weakened by each of those phages.
Based on that analysis, Rotman and her colleagues developed a mixture of five phages that each targeted different components of the bacteria. In culture dishes as well as mice, this phage cocktail made antibiotic-resistant Klebsiella bacteria more likely to be attacked by the immune system and, in some cases, more susceptible to treatment with antibiotics. However, in other cases, the bacteria became more antibiotic resistant 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 an 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 ability of the cocktail to kill Klebsiella. In mice, the mixture effectively killed or weakened Klebsiella. The researchers observed co-evolution between the bacteria and phage in the mouse intestines, where the Klebsiella evolved to evade phage attack and the phage countered to better infect the altered bacteria.
Mimee's lab group is continuing experiments to better understand how different phage and bacteria pairs interact with each other and how the presence of other phages and bacteria – naturally found in the human body—influences that. 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 sort out the complexities of phages and move them closer to the clinic," says Mimee.
Citation: "Rapid design of bacteriophage cocktails to suppress the burden and virulence of gutresident carbapenem-resistant Klebsiella pneumoniae," Rotman et al, Cell Host & Microbe, October 4, 2024. DOI: https://doi.org/10.1016/j.chom.2024.09.004
Funding: National Science Foundation, National Institutes of Health, Arnold and Mabel Beckman Foundation, BRaVE Phage Foundry at Lawrence Berkeley National Laboratory.
