U of T start-up's breakthrough molecule: Eliminating pathogens without harming oral microbiota
The human microbiome influences our immune system and overall health. Our mouths have the second largest and most diverse microbiota after the gut, harboring over 700 species of bacteria. With this abundance of microbes within us, there is a rising interest in exploring their health-promoting properties.
Professor Michael Glogauer, and Dr. Abdelahhad Barbour, molecular microbiologist, discovered a new biotherapeutic molecule, patented as Salivaricin 10 (Sali10), produced by a strain of oral probiotic bacteria called Streptococcus salivarius SALI-10, that kills infectious pathogens while promoting a healthy microbiome. Their recent discovery, published in the prestigious Proceedings of National Academy of Science journal, opens the door to an alternative to conventional antibiotic treatments and is a novel solution to prevent infectious diseases.
Standing out from conventional antibiotics
Conventional antibiotics, mainly isolated from soil-derived microorganisms, generally have a broad spectrum of antimicrobial activity which kills good and bad bacteria alike. What is promising about Sali10 is that it effectively targets infectious pathogens while also maintaining important oral microbiota. “Sali10 kills oral pathogens that cause periodontal diseases as well as many multi-drug resistant respiratory pathogens that cause pneumonia.” says Glogauer.
“Unfortunately, less than three per cent of the human population has indigenous S. salivarius that can produce Sali10 in their mouth. We hope to create biotherapeutics in the form of beneficial bacteria with drug-like properties that eventually people can rinse with, or eat foods with it, so that their oral microbiome is tipped to a healthy side. The S. salivarius bacteria themselves are a drug delivery device due to their probiotics properties which enable them to colonize the mouth and produce and release Salivaricin 10 peptides.”
The search for beneficial bacteria
Glogauer and Barbour co-founded Ostia Sciences Inc, a University of Toronto affiliated start-up, in 2020. “We look for beneficial bacteria in the mouth, called commensals with probiotic properties. They are the opposite of pathogens and keep us healthy.” says Glogauer.
This project began with isolating Streptococcus salivarius from healthy people’s mouths and observing how these commensals were impacting bacterial pathogens and the innate immune responses. “S. salivarius is indigenous to the human oral cavity and the gut and it co-evolved within the human body over hundreds of thousands of years.” says Barbour.
Some specific strains of commensals can produce special peptides called lantibiotics (antibiotics that have lanthionine) that can impair pathogens’ colonization and promote healthy microbiomes. Lantibiotics produced by S. salivarius are called salivaricins.
“We discovered a new class of these molecules called Salivaricin 10 with novel structural and biological properties."
"We observed that this previously unidentified structural class of lantibiotics is responsible for many immunomodulatory activities beyond the antimicrobial capacity.” says Barbour.
A breakthrough molecule
In fact, they observed that Sali10 molecules were a chemoattractant to neutrophils, which means that they recruited more immune cells to help fight off infections. Sali10 enhanced phagocytosis, the process by which specialized immune cells like neutrophils engulf and break down harmful substances like bacteria and viruses. It was also observed that Sali10 reduced inflammation through the promotion of anti-inflammatory macrophages.
“We wanted to know structurally why these lantibiotic peptides had this incredible multi-functionality. Why was this molecule able to do what it was doing making it superior to other lantibiotics?” says Barbour.
The research team applied structural biology analysis and discovered that Sali10 molecules had a phosphorylation site on the N-terminal region of the peptides. “Sali10 is the first phosphorylated lantibiotic ever discovered. This novel structural feature is responsible for the immunoregulatory function” says Barbour.
This discovery also opens the question of phosphorylated lantibiotics in other human microbiomes and their role in promoting health. “Having demonstrated the efficacy of salivaricin 10 in both in vitro and in vivo models, we plan to commence human clinical trials in the near future to establish its safety and efficacy clinically.” says Barbour.
Learn more about research at the Faculty of Dentistry.
Written by Nina Ambros
Photo credit: Jeff Comber, IITS