For UTIs, Manipulate, Not Eliminate, the Bad Bugs

By Keith Gillogly

But for catheterized individuals with persistent urinary tract infections, this simple rule doesn’t always apply.

Clear bad bacteria from the bladder, and they’ll quickly repopulate. What’s more, pathogens such as E. coli can dwell for weeks without causing infection.

“The whole goal in the past has been, let’s get rid of the bacteria we think are causing the infection,” says Chelsie E. Armbruster, PhD. “But the more we learn as we study these polymicrobial scenarios, what we think is causing the infection is not always the case.”

Armbruster, associate professor of microbiology and immunology at the Jacobs School of Medicine and Biomedical Sciences, has long studied bacterial populations in the urinary tract and their link to catheter-associated urinary tract infection, or CAUTI.

To continue investigating these polymicrobial communities, she recently received a five-year, $3.75 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health. Her project is titled “Impact of Polymicrobial Interactions and Within-Host Adaptation on CAUTI Pathogenesis.”  

CAUTIs are among the most common health care-associated infections worldwide and can be both debilitating and deadly. The indwelling catheter acts as a scaffold for growing bacterial biofilms, or communities of bacteria that stick to a surface, bolstering antibiotic resistance. Even when antibiotics can clear the bugs, Armbruster says, bacterial reservoirs quickly repopulate the pathogens.

Curiously, Armbruster and her colleagues observed that similar bacteria appear in catheterized urine — whether or not an infection is present. So why do some individuals harboring pathogens remain stable and asymptomatic while others develop debilitating infections?

To find out, she and her team are focusing on the three most common and persistent pathogenic colonizers of the catheterized urinary tract — E. faecalis, P. mirabilis, and E. coli — to understand how these microbes’ interactions affect biofilm formation and antibiotic resistance.

Microbes and pathogens within the urinary tract are co-dependent. Depending on their nutrient intake, Armbruster explains, they secrete different amino acids that other bacteria in turn consume.

Armbruster and her team, including postdoctoral fellow Benjamin C. Hunt, PhD, will continue exploring how these microbes’ metabolic interactivity can affect virulence factors and formation of biofilms using an external model that mimics the human urinary tract.

The researchers will use a multiomics approach, which combines biological data — like genes, proteins and metabolites — to investigate how different combinations of the three target species could affect catheter colonization. A mouse model of CAUTI will be used to further study how different combinations affect pathogenesis.

Armbruster will also investigate how the target bacteria “cooperate,” work that’s been the focus of doctoral student Steven Taddei. When E. coli, for example, first populate the urinary tract, they appear to set up an environment conducive to other microbes coming in and forming more robust biofilms.

“We know when all three species are together, they make a much more robust biofilm than when alone,” Armbruster says.

If the researchers identify metabolic signaling that increases virulence, it could be possible to design treatments (like a locally applied catheter wash, as opposed to antibiotics) that interrupt this process. 

Populations of pathogens living in the urinary tract for weeks on end are not static — they divide and divide, amassing a host of genetic changes. These mutations can make the bacteria more pathogenic or, conversely, less.

Building on work by doctoral student Namrata Deka, Armbruster and her colleagues will track and investigate genotypic and phenotypic changes across the three bacterial species from urine specimens with persistent colonization.

“There are lots of variables we need to look at,” Armbruster says. “Where are these mutations occurring? Are there commonalities between isolates from different patients? And what’s driving differences and pathogenic potential?”

By studying these genetic changes, it could be possible to determine and then knock out genes and pathways bolstering pathogenicity, Armbruster says.   

Armbruster began studying bacterial communication and biofilms as a doctoral student, focusing on middle ear infections in children. She shifted her research to catheter biofilms as a postdoc, an understudied issue affecting underserved and older populations.

“I wanted my work to be meaningful for patients. I really wanted to be anchored in some sort of human problem where I could see a potential translation,” she says

Seeking to understand polymicrobial communities is a “tricky problem,” Armbruster says. “But I like a puzzle.” And she’s hardly without help. Armbruster credits the students and researchers in her lab with developing the ideas needed to continue investigating.

“This grant would not have happened without them. They all brought interesting new ideas that ultimately pulled this all together.”