A groundbreaking discovery in the fight against antibiotic-resistant E. coli has emerged, offering a glimmer of hope in the battle against this insidious pathogen. Researchers at the University of Alberta have identified a novel drug target, a protease known as GlpG, which plays a pivotal role in the bacteria's ability to infect human cells and resist treatment. This breakthrough could potentially revolutionize the treatment of urinary tract infections (UTIs), which claim nearly 250,000 lives annually and are becoming increasingly resistant to antibiotics.
The research, published in Nature Communications, reveals how GlpG, located in the cellular membrane, is central to the bacteria's virulence. Principal investigator Joanne Lemieux explains, "This protease is essential for the formation of pili, hair-like appendages on the bacterial surface that aid in adhering to tissues. It also facilitates the creation of biofilms, protective layers that shield bacteria from the immune system and antibiotics, leading to persistent and chronic infections."
The team's experiments demonstrated that inhibiting GlpG protease in pathogenic E. coli prevented bacterial adhesion and invasion into bladder and kidney cells. It disrupted the formation of biofilms, both existing and those in the early stages of development. Lemieux's lab is now focused on developing new drugs that specifically target GlpG while leaving beneficial E. coli in the gut unharmed.
The urgency of addressing antimicrobial resistance is underscored by the alarming global death rate increase of 140% in UTIs between 1990 and 2019, largely due to the rise of antibiotic resistance. Lemieux warns, "Antimicrobial resistance is now a global emergency. By 2050, deaths due to antimicrobial resistance are anticipated to equal those from cancer."
The implications of this discovery extend beyond UTIs. Pathogenic E. coli is implicated in inflammatory bowel disease, Crohn's disease, and ureter stent blockages, which currently require surgical replacement. Lemieux notes, "UTI infections don't just affect women. Pediatric patients and individuals with catheters, both male and female, are susceptible. Even those surviving kidney cancer treatment and kidney disease can succumb to urosepsis."
Protease inhibitors, already in use for other diseases like blood disorders, HIV, and COVID-19, offer a promising avenue for treating E. coli infections. Lemieux collaborated with colleagues from biochemistry, medical microbiology, and pediatrics for this research. The first author, Jimmy Lu, conducted 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.
While drug development can take up to a decade, Lemieux's lab gained valuable experience during the pandemic and holds several patents for new antiviral drugs. She emphasizes the urgency of investing in antibacterial countermeasures, stating, "UTI is an infectious disease so common that people take for granted that there will be an antibiotic available. Understanding the virulence factors for pathogenic E. coli is the first step in developing effective treatments."
This research, funded by various organizations, including the Canada Foundation for Innovation and the Natural Sciences and Engineering Research Council of Canada, marks a significant step forward in the fight against antibiotic-resistant E. coli, offering hope for a healthier future.
