Researchers at McMaster University have discovered how a widespread but previously mysterious group of bacterial proteins kill a broad range of other bacteria — a finding that could someday reshape how we treat bacterial infections.
The discovery, detailed recently in the Proceedings of the National Academy of Sciences, comes amid growing concern about antimicrobial resistance (AMR), a global health crisis driven by the spread of drug-resistant bacteria.
Many bacteria produce toxic proteins to eliminate nearby competitors; however, these antibacterial proteins have long been thought to act only against a very narrow range of closely related species, making them unviable as an alternative to traditional antibiotics.
Until now, none of these proteins were known to target bacteria from multiple groups.
“For years, the field has been unanimous about the fact that antibacterial proteins are rarely broad-spectrum,” explains senior author John Whitney, an associate professor in McMaster’s Department of Biochemistry and Biomedical Sciences.
All previously known antibacterial proteins depend on a unique “receptor” — a precise molecular target on the surface of susceptible bacteria — to gain entry and exert their bactericidal effects, Whitney says.
Because these receptors vary so much between species, though, each protein typically only works against a single type of bacterium.
But the proteins characterized by Whitney’s lab completely buck that rule — they kill a wide variety of bacterial species, regardless of what receptors those cells have.
Indeed, researchers in Whitney’s lab, led by MD/PhD student Jake Colautti, tested one of these proteins by applying it to lawns of pathogenic bacteria, including Listeria (which causes listeriosis), Staphylococcus (staph infections), and Enterococcus (urinary tract infections).
Within a day, the bacterial colonies were eliminated.
“I was very skeptical that the experiment would work,” says Whitney, a member of the Michael G. DeGroote Institute for Infectious Disease Research at McMaster.
“I’ve spent my entire career studying antimicrobial proteins and I’ve never seen anything like it.”
Another mystery that the team addressed is how such large molecules can penetrate bacteria. Compared to traditional antibiotics, antibacterial proteins are massive — often thousands of times larger.
And while bigger may sound better when it comes to killing bacteria, Whitney says that size can actually be a major problem at the molecular level.
“Most antibiotics function by getting inside bacteria and disrupting essential processes,” he explains.
“To get inside, they typically slip through tiny pores in the bacteria — so, the larger the molecule, the more challenging that is. In the case of proteins, they are usually far too big to enter bacteria on their own.”
To overcome this, many bacteria have evolved specialized secretion systems — molecular “needles” that forcibly inject these toxic proteins into neighbouring cells. But these systems require prolonged physical contact between different bacteria, which also hurts the therapeutic potential of these molecules.
But the McMaster team found that their proteins work completely differently. Rather than being injected, they are secreted freely into the environment alongside a helper enzyme called a protease, which activates them for attack.
Once activated, the proteins can slip directly across the membrane of susceptible bacteria without needing a specific receptor or the help of an injection system.
This unusual mechanism, powered by the target cell’s own membrane energy, allows the proteins to kill many different species of distantly related bacteria.
While these specific proteins are unlikely to become therapeutics in the near future, the research team believes that the new findings expand our understanding of how bacteria wage war and may ultimately inspire new approaches to tackling antibiotic resistance.
“These findings reveal an entirely new way that proteins can be used to kill bacteria,” says Colautti, who is first author on the new paper.
“We hope that understanding how these proteins work will help guide future efforts to design protein-based antibacterial agents.”