New drug target offers hope in fight against antibiotic-resistant E. coli

A University of Alberta research team has identified a new drug target to treat harmful E. coli bacteria — which cause nearly 250,000 deaths a year from urinary tract infections (UTI) and are becoming increasingly resistant to antibiotics.

Recently published research in Nature Communications shows how the protease known as GlpG, located in the cellular membrane, is central to the bacteria’s ability to infect human cells and resist treatment.

“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,” explains principal investigator Joanne Lemieux, professor of biochemistry and vice-dean of research for the Faculty of Medicine & Dentistry. “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.”

The team showed that when they inhibited GlpG protease in pathogenic E. coli, they prevented bacterial adhesion and invasion into bladder and kidney cells. It stopped the formation of protective biofilms and eradicated biofilms that had started to form.

Lemieux’s lab is now focused on developing new drugs that will inhibit the protease in pathogenic E. coliwhile leaving helpful E. coli in the gut untouched.

The global death rate due to UTIs increased by 140 per cent between 1990 and 2019 largely because of the rise of resistance to classes of commonly prescribed antibiotics.

Lemieux says antimicrobial resistance is now a global emergency.

“It’s anticipated that by 2050, deaths due to antimicrobial resistance will equal those due to cancer,” Lemieux says, noting the World Health Organization has listed E. coli as a pathogen of critical concern.

“UTI infections don’t affect just women,” Lemieux says. “There are pediatric patients with chronic UTIs. Both male and female patients with catheters get urinary tract infections. People are surviving kidney cancer treatment and kidney disease, but then succumbing to urosepsis.”

Lemieux says pathogenic E. coli are also implicated in inflammatory bowel disease, Crohn’s disease and ureter stent blockages, which currently require surgical replacement.

She says it’s encouraging to be able to identify a new target against the bacteria because up to one-fifth ofE.coli infections are already resistant to antibiotics. Protease inhibitors are already in use as medications to treat other diseases such as blood disorders, HIV and COVID-19.

Lemieux collaborated with colleagues from biochemistry, medical microbiology and pediatrics for this research. The paper’s first author, Jimmy Lu, did the work as part of his PhD thesis and is now a Mitacs post-doctoral fellow with industry partner Applied Pharmaceutical Innovation, working in Lemieux’s lab.

She admits drug development can take up to 10 years, but her lab gained experience in this area during the pandemic and holds several patents for new antiviral drugs.

”UTI is an infectious disease that’s so common people take for granted that there’s going to be an antibiotic there for them,” Lemieux says. “It is urgent that we invest in developing antibacterial countermeasures now, because the drug discovery pipeline does take a long time. Understanding the virulence factors for pathogenic E. coli is the first step.”

M. Joanne Lemieux is executive director of the PRAIRIE Hub for Pandemic Preparedness. She is a member of the Women and Children’s Health Research Institute (WCHRI), the Neuroscience and Mental Health Institute, the Cancer Research Institute of Northern Alberta and the Li Ka Shing Institute of Virology. Funding for this research came from the Canada Foundation for Innovation, the Natural Sciences and Engineering Research Council of Canada and the Alberta Graduate Excellence Scholarship. The work was also supported by the Stollery Children’s Hospital Foundation and Alberta Women’s Health Foundation through WCHRI and Striving for Pandemic Preparedness – The Alberta Research Consortium.