A groundbreaking discovery at the University of Alberta offers a glimmer of hope in the battle against antibiotic-resistant E. coli, a formidable foe responsible for over 250,000 deaths annually due to urinary tract infections (UTIs). This crisis is exacerbated by the bacteria's growing resistance to antibiotics, a global emergency that demands our immediate attention.
The research, published in Nature Communications, unveils a critical player in the bacterial invasion: GlpG, a protease located in the cellular membrane. This protease is essential for the formation of pili, tiny hair-like structures that enable E. coli to adhere to human cells and cause infection. Moreover, GlpG plays a pivotal role in the creation of biofilms, protective shields that safeguard bacteria from the immune system and antibiotics, leading to persistent and chronic infections.
The research team, led by Professor Joanne Lemieux, demonstrated that inhibiting GlpG protease in pathogenic E. coli effectively prevents bacterial adhesion and invasion into bladder and kidney cells. This inhibition also disrupts the formation of biofilms, eradicating any that have already begun to develop.
Lemieux's lab is now dedicated to developing new drugs that specifically target GlpG protease in pathogenic E. coli while leaving the beneficial E. coli in the gut unharmed. This precision approach is crucial, as the global death rate from UTIs has surged by 140% since 1990, largely due to the rise of antibiotic resistance.
"Antimicrobial resistance is a global emergency," Lemieux emphasizes, adding that by 2050, deaths due to antimicrobial resistance are projected to match those caused by cancer.
UTIs, Lemieux points out, are not limited to women. Pediatric patients, male and female catheter users, and individuals surviving kidney cancer treatment and kidney disease are all at risk. Pathogenic E. coli is also implicated in inflammatory bowel disease, Crohn's disease, and ureter stent blockages, currently requiring surgical intervention.
The identification of GlpG as a new target is particularly promising, as up to one-fifth of E. coli infections are already resistant to antibiotics. Protease inhibitors, already in use as medications to treat blood disorders, HIV, and COVID-19, offer a potential solution.
Lemieux collaborated with colleagues from biochemistry, medical microbiology, and pediatrics for this research. The first author, Jimmy Lu, conducted this work as part of his PhD thesis and is now a Mitacs post-doctoral fellow with industry partner Applied Pharmaceutical Innovation, continuing his research in Lemieux's lab.
While drug development can be a lengthy process, taking up to a decade, Lemieux's lab gained valuable experience during the pandemic and holds patents for new antiviral drugs.
"UTI is an infectious disease so common that people assume antibiotics will always be available," Lemieux says. "It is urgent that we invest in developing antibacterial countermeasures now, as the drug discovery process is lengthy. Understanding the virulence factors of pathogenic E. coli is the crucial first step."
This research offers a ray of hope in the fight against antibiotic-resistant E. coli, but it also underscores the urgency of addressing antimicrobial resistance on a global scale. With further research and development, we may be able to turn the tide against this deadly pathogen.
