Ijlal Amir Researchers at the University of Alberta have identified a promising new drug target that could help combat antibiotic-resistant Escherichia coli (E. coli), a major cause of urinary tract infections (UTIs) responsible for nearly 250,000 deaths globally each year.
Drug target protease GlpG
As antibiotic resistance continues to rise, treating common infections like UTIs is becoming increasingly difficult. The research, led by Joanne Lemieux, professor of biochemistry and vice-dean of research in the faculty of medicine and dentistry, focuses on a protein called GlpG, a protease embedded in the bacterial cell membrane.
“This protease in pathogenic E. coli is essential for the formation of virulence factors known as pili, little hair-like appendages that sit on the bacterial surface and help the bacteria adhere to tissues,” Lemieux explained. “It also plays a key role in the formation of biofilms that protect bacteria from the immune system and antibiotics, leading to persistent and chronic infection.”
Pili allows bacteria to attach to human cells, while biofilms act as a protective shield, making infections harder to treat. By targeting GlpG, the research team discovered they could effectively disrupt both processes.
Using a combination of cell models and human kidney organoids, the team demonstrated that inhibiting GlpG prevented bacteria from adhering to and invading bladder and kidney cells. Notably, the approach also stopped biofilms from forming and even eliminated ones that had already developed.
“That’s quite exciting,” Lemieux said. “Biofilms are often very resistant to antibiotics and are associated with chronic infections. Being able to both prevent and eradicate them opens up new possibilities for treatment.”
Interestingly, GlpG was not initially an obvious target. Lemieux’s lab had been studying the protein for years without fully understanding its function.
“It appeared to have no main function, deleting the gene didn’t kill the bacteria,” she said. “We wanted to explore what other proteins it interacts with, and we were quite surprised to find that it actually played a role in developing virulence factors and presenting them on the bacterial surface.”
This discovery aligns with the lab’s broader expertise in studying proteases and their role in disease. Rather than killing bacteria outright, targeting GlpG weakens the bacteria’s ability to cause infection, an approach known as anti-virulence therapy.
Unlike traditional antibiotics, which kill both harmful and beneficial bacteria, this strategy could leave helpful microbes in the body intact.
“When we inhibit this protease, we don’t kill the bacteria,” Lemieux said. “That’s important because it means we can potentially preserve the natural microbiome of the beneficial bacteria in places like the gut while still preventing infection.”
Urgent public health issue due to antimicrobial resistance
The need for new treatment approaches is urgent. According to Lemieux, approximately five million people globally were affected by antimicrobial-resistant infections in 2021. It has been estimated that deaths due to antimicrobial resistance could rival those from cancer by 2050.
“Simple infections that people consider treatable are becoming harder to manage,” she said. “As people age or have compromised immune systems, their ability to fight infections decreases, making effective treatments even more critical.”
While UTIs are often associated with women, Lemieux emphasized that they affect a wide range of populations.
“There are pediatric patients with chronic UTIs. Both male and female patients with catheters get urinary tract infections. People are surviving serious conditions like kidney cancer, but then succumbing to infections like urosepsis,” she said.
Beyond UTIs, pathogenic E. coli is also linked to conditions such as inflammatory bowel disease and Crohn’s disease. The findings may also have broader implications for other infections involving biofilms, including those seen in cystic fibrosis.
Despite the promise, translating this discovery into a clinical treatment will take time. Drug development can take up to a decade and involves ensuring that potential compounds are safe, effective, and specific to the target.
Next steps to further research
The next steps for the research team include collaborating with medical chemists to develop small-molecule inhibitors that specifically target GlpG without causing off-target effects. The team is also integrating artificial intelligence with traditional drug discovery methods to accelerate the process.
“It’s a long-term project, but we’re building a strong interdisciplinary team to move this forward,” Lemieux said.
She also highlighted a broader challenge in public health: a misconception that existing antibiotics are sufficient.
“There’s a tendency to think we already have enough antibiotics,” she said. “But antibiotic resistance is a silent pandemic. It’s urgent that we invest in developing new antibacterial strategies now, because the drug discovery pipeline takes a long time.” Thus, she stated “we’re going to have a need for novel antibiotics because of that increasing growth of resistance globally.”
As resistance continues to rise, discoveries like this offer a step toward staying ahead of evolving bacterial threats and rethinking how infections are treated in the future.
