At a time when the news about the antibiotic pipeline hasn't been great, a team of Canadian and US scientists say they've made a discovery they hope could lead to an entirely new class of antibiotics.
The discovery is an antibiotic peptide that was identified in bacteria from soil that had been grown for a year in a lab at McMaster University in Ontario. After observing that a substance produced by a bacterium from one of the soil samples showed antibacterial activity against multidrug-resistant bacterial species, researchers from McMaster and the University of Illinois at Chicago (UIC) were able to identify the peptide, which they named lariocidin, as the molecule responsible for the activity.
Even better, they discovered that lariocidin—named for its knotted, lasso-like chemical structure—has a unique mechanism of action that differentiates it from other antibiotics. They also found that it's active against a wide spectrum of bacteria, isn't toxic to human cells, and works in an animal model of infection.
The findings were published last week in Nature.
Although it's just the beginning of a long road, Gerry Wright, PhD, who directs the Michael G. DeGroote Institute for Infectious Disease Research at McMaster, says he's "pretty chuffed" about what they've found.
"This is exactly where you want to be at the beginning of this journey," Wright said. "Now to see whether or not we can turn it into a drug."
'It's hard to find something new'
The discovery emerged from work that Wright and members of his lab have been pursuing for several years—looking for naturally occurring antibiotic resistance in microbes found in the environment. Over the years they've collected as many as 13,000 microbes, hoping that some, in addition to producing resistance genes, might also harbor some antimicrobial compounds.
As Wright explains, the environment has been the source of some of our most commonly used antibiotics, from the original antibiotic, penicillin—which was discovered in mold growing in a petri dish in 1928—to daptomycin, identified in a soil sample from Turkey in the late 1980s. But by the 1980s, most pharmaceutical companies were pivoting away from environmental sources of antibiotics, because they had already found the low-hanging fruit, and new discoveries were becoming more difficult.
"They kept finding penicillin or streptomycin or tetracycline over and over again," Wright said. "It's easy to find those molecules. It's hard to find something new."
Hoping to find some "new stuff from the old stuff," Wright and his colleagues spent a year growing microbes from soil collected from the backyard of one of the team members. While several of the fast-growing microbes died off, they found that an extract from a slower-growing, often overlooked bacterium called Paenibacillus showed potent antibacterial activity against Escherichia coli and a multidrug-resistant strain of Acinetobacter baumannii.
It's easy to find those molecules. It's hard to find something new.
Initially, they thought the activity could be explained by the fact that Paenibacillus naturally produces an older antibiotic called colistin. But using reverse-phased chromatography, they were able to separate out the compounds from the Paenibacillus extract—what Wright calls "goo"—and identify the lasso peptide lariocidin as a molecule with its own antibacterial activity.
"If we had just done traditional testing, we would have missed this new molecule because the overwhelming product of the 'goo' is this old drug called colistin," he said.
A new target
The next step was to examine how lariocidin works. With the help of experts in ribosome chemistry at UIC, they found that the peptide inhibits bacterial growth by binding to the bacterial ribosome, which is responsible for protein synthesis. That wasn't necessarily surprising, since the ribosome is a key target for many classes of antibiotic.
But what was surprising is the discovery that lariocidin binds at a different site on the ribosome than other antibiotics, so it's not susceptible to the same resistance mechanisms that bacteria use to fight off those other drugs.
"Finding new spots that other antibiotics haven't already selected for their binding is increasingly harder to do," Wright said. "So that was fantastic."
"In the antibiotic discovery field, you want a weapon which kills by targeting something different than the previous ones did before," study co-author Yury Polikanov, PhD, an associate professor of biological sciences at UIC, explained in a university press release. "Otherwise, previously used protections will automatically lead to defense against the new molecule."
Further testing revealed lariocidin showed no toxicity to human cells, readily inhibited growth of both gram-positive and gram-negative bacteria inlab tests, and demonstrated potent activity in mice infected with A baumannii.
They also discovered a double-knotted variant of the peptide—lariocidin B— that might have even better drug-like properties.
A long road ahead
Wright is under no illusion that the road ahead will be easy. What the team is working on now is the process of taking lariocidin from a natural product to a clinical product. They're deconstructing the peptide and rebuilding it with additional elements to increase its antibacterial activity and optimize its potential. There's also a lot of pharmacologic work that needs to be done to get to the point where lariocidin could be tested in people.
It's a process that will take several years and require significant funding. And that funding isn't likely to come from the pharmaceutical industry.
"It's not like every drug company in the world is breaking down the doors trying to do antibiotic discovery," Wright said. "It's a very challenging environment to be in."
If we work together, we can do great things.
But he's excited about the strategies they've developed, which he believes could lead to the discovery of more molecules with new modes of action against bacteria. He also sees signs of hope in the cross-border collaboration with UIC scientists, which was funded by both the Canadian and US governments.
"I think is a good-news story," Wright said. "If we work together, we can do great things."
