New Drug Target Identified for Antibiotic-Resistant E. Coli Infections
University of Alberta researchers identified GlpG protease as a new drug target for treating antibiotic-resistant E. coli, which causes 250,000 UTI deaths annually. Inhibiting the protease prevented bacterial adhesion and biofilm formation in laboratory tests.
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.
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. The World Health Organization has listed E. coli as a pathogen of critical concern. It's anticipated that by 2050, deaths due to antimicrobial resistance will equal those due to cancer.
Up to one-fifth of E. 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.
"UTI infections don't affect just women," the principal investigator 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." Pathogenic E. coli are also implicated in inflammatory bowel disease, Crohn's disease and ureter stent blockages, which currently require surgical replacement.
The lab is now focused on developing new drugs that will inhibit the protease in pathogenic E. coli while leaving helpful E. coli in the gut untouched. 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. Drug development can take up to 10 years, but the lab gained experience in this area during the pandemic and holds several patents for new antiviral drugs.
The research team collaborated with colleagues from biochemistry, medical microbiology and pediatrics. 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.