In every backyard, park, and playground on Earth, the ground is teeming with a type of bacteria called Streptomyces — one of the most abundant organisms on the planet. While these dirt-dwelling microbes are known for producing that earthy odor that fills the air after rainfall, that familiar scent is only the tip of their chemical-producing iceberg.
Streptomyces are, in effect, natural pharmaceutical factories, responsible for producing many of the anticancer compounds, immunosuppressants, and antibiotics used in clinics worldwide. But a new study published in the journal Nature Microbiology suggests that their chemical repertoire is even more complex than previously understood.
Researchers at McMaster University, Boston Children's Hospital, and Harvard Medical School, with collaborators from Stockholm University in Sweden and Yale University, have identified and characterized a new class of Streptomyces-produced toxins that are very distantly related to the deadly toxin that causes diphtheria, a serious and contagious infection, in humans.
Despite their structural similarities to the diphtheria toxin, though, these newly discovered toxic proteins do not cause human disease. They do, however, kill a broad range of insects.
"These toxins, which we've called Streptomyces antiquus insecticidal proteins, or SAIPs, only affect insect cells," explains Cameron Currie , a professor in McMaster's Department of Biochemistry and Biomedical Sciences and co-lead on the new study.
To understand exactly why SAIPs are only toxic to insects, researchers used a genome-editing technology called CRISPR to identify the host factors required for toxicity. By systematically knocking out the genes of insect cells, they pinpointed a surface protein called 'Flower.' While versions of this gene exist in other organisms, the insect-specific version is the only known receptor for SAIPs. These toxins cannot enter cells without it, which is why they have no effect on humans.
Through bioinformatic, genomic, and evolutionary analyses, the research team then traced the emergence of these previously unknown toxins through time, to determine when Streptomyces evolved the ability to produce them. They found that SAIPs are in fact ancient, dating back more than 100 million years.
For Currie, a member of the Michael G. DeGroote Institute for Infectious Disease Research and McMaster's Jarislowsky Chair in Pandemic Research, the toxins' ancient history suggests a possibility that they have potentially played a role in shaping human disease, although he notes that remains speculative.
"We know that the bacteria that causes diphtheria acquired its toxin from another species of bacteria long ago, so it's possible that these Streptomyces toxins were the crucible for the eventual emergence of the diphtheria toxin," he says.
Crucially, not all species of Streptomyces produce these toxins — in fact, the vast majority of species live harmoniously in, on, and around insects. The capability, researchers say, appears to be restricted to a few specific lineages within the massive genus.
"Streptomyces have primarily been known to have mutualistic relationships with insects, but we have discovered a clade of strains that are likely insect pathogens," explains Min Dong, a researcher at Boston Children's Hospital, an associate professor at Harvard Medical School, and co-lead on the new study.
These strains, researchers say, have evolved a highly specialized role in nature.
"They don't just kill insects — they are also remarkably efficient at consuming them, using their dead hosts as a source of critical nutrients," says Currie, who also collaborated with Harvard's Norbert Perrimon on the study.
As these specialized Streptomyces strains break down insect tissue, they simultaneously produce potent antimicrobial chemicals — likely to ward off competing microbes drawn to the same resource. As such, the research team believes that these insect-associated strains of Streptomyces could be a largely untapped source of new antibiotics or other medically useful molecules. Already, in past research, the Currie Lab has identified a number of promising antibiotics produced by other Streptomyces strains, which makes him optimistic about the clinical relevance of these new chemicals.
Beyond that, Currie notes that the discovery of a SAIPs is significant because bacterial toxins can have implications well outside of their role in disease. He notes that botulinum toxin — commonly known as botox — has several medical and cosmetic applications, while other bacterial toxins have been harnessed for uses in immunology, agriculture, and biotechnology.
"Right now, this is a basic science discovery, but a discovery that may have some really practical applications in the future," he says. "A toxin like this could potentially help control vectors of human disease, like mosquitos, which can transmit malaria and West Nile virus, or perhaps be used to protect crops from insect pests. It's possible it could be used in a number of different ways."
Currie and his collaborators have already patented their discovery and are now beginning to explore potential commercialization pathways for the toxin — particularly in agriculture, where insect toxins are typically in high demand.
In the meantime, the research team is investigating how SAIPs behave in more complex biological settings, including in experimental systems involving crickets and mealworms — organisms that serve as tractable models for studying infection and toxicity. These studies are also allowing researchers to isolate the antimicrobials secreted by toxin-producing strains of Streptomyces, which will help them better understand their clinical potential.
But regardless of how that follow-on work transpires, Currie says the discovery alone is a significant research achievement, and one that signals just how much there is left to learn about bacteria.
"That we have found something so novel in one of the world's most abundant and well-studied groups of bacteria underscores how little we actually know about them," he says. "This toxin stands as a powerful reminder that bacteria are incredibly diverse organisms, with capabilities that continue to surprise us."
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