Megacluster of Antibiotic Genes Discovered in Soil Bacteria Targets Biotin Pathway to Combat Superbugs
核心洞察
Researchers at McMaster University identified a "megacluster" of genes in *Streptomyces (搜索)* bacteria that produces four distinct antibiotics and a biotin-binding protein, all targeting the essential vitamin B7 pathway.
The four antibiotic families—stravidins (搜索), acidomycin (搜索), α-Me-KAPA, and the newly discovered dapamycins (搜索)—attack different stages of biotin production, uptake, and use, making resistance harder to evolve.
Two of the compounds proved highly effective against multidrug-resistant *E. coli* in animal infection models, demonstrating early therapeutic potential.
A landmark study published in Nature has revealed an extraordinary "megacluster" of genes in common soil bacteria that orchestrates a coordinated, multi-pronged antibiotic assault on rival microbes—a discovery that could reshape how researchers approach the development of drugs against multidrug-resistant infections.
Scientists at McMaster University, led by biochemist Eric Brown, identified an unusual stretch of DNA spanning 65,808 base pairs in Streptomyces (搜索) bacteria that encodes four distinct families of natural product antibiotics, all converging on a single vulnerability: biotin, also known as vitamin B7, an essential nutrient required by most bacteria for survival.
"It's really sinister," said Brown, a professor of biochemistry and biomedical sciences at McMaster and principal investigator on the study. "Picture one of these molecules taking out the power, another taking out communications infrastructure, another cutting off water systems, and another blocking critical roadways. It's an all-out, strategic, and coordinated attack on rival bacteria."
Four Antibiotic Families, One Target
The megacluster produces five compounds in total—four antibiotics and a protein—that target different stages of biotin production, uptake, and utilization. The antibiotic families include stravidins (搜索), a previously known biotin-targeting class; acidomycin (搜索); α-Me-KAPA; and a newly discovered family of compounds the team named dapamycins (搜索). The gene region also contains genes for streptavidin (搜索), a protein known to bind biotin, effectively sequestering the nutrient from competing cells.
That four distinct families of antibiotics all work together to attack the same metabolic pathway in different ways is unique, but that all four are enabled by genes co-located in the genome is, according to Brown, "unheard of."
"The proteins are made to bind up available biotin, while their neighbouring antibiotics prevent competing cells from getting to it first," Brown explained.
Hiding in Plain Sight
The discovery is particularly striking given that Streptomyces (搜索) is one of the most extensively studied bacterial genera, having yielded numerous antibiotic compounds including streptomycin, the first effective antibiotic against tuberculosis. Yet this megacluster had remained hidden.
"They've discovered something new in a system so extensively studied—hidden in plain sight," said Mark Blaskovich, who works on antibiotic development at the University of Queensland in Brisbane, Australia.
Brown and his team had been investigating biotin metabolism as a potential antibiotic target for decades. While studying stravidins (搜索), they found that the genes encoding these compounds form part of a larger set of DNA involved in biotin formation—a finding that ultimately led to the characterization of the entire megacluster.
The team confirmed the role of these genes by cloning the 65,808-base-pair DNA section containing the megacluster and inserting it into a laboratory strain of Streptomyces (搜索).
Evolutionary Conservation and Therapeutic Potential
Analysis revealed that the anti-biotin antibiotic megacluster is widespread across different species of Streptomyces (搜索), suggesting the strategy evolved long ago and has been conserved over millions of years.
"Our analysis showed that this megacluster is even more widespread across Streptomyces (搜索) genomes than the genes responsible for making streptomycin—one of the classic antibiotics discovered from these bacteria back in the 1940s," said Rodion Gordzevich, a postdoctoral fellow in Brown's lab and co-first author of the study alongside former Wright Lab postdoctoral fellow Min Xu.
In animal models of infection, two of the newly characterized compounds proved highly effective against multidrug-resistant E. coli, offering an early indication that the strategy could have real therapeutic potential.
A New Paradigm for Combating Resistance
Antibiotic-resistant infections are projected to kill approximately 39 million people between 2025 and 2050, making the search for antibiotics with new modes of action critically urgent. Because the megacluster's compounds attack multiple points in the same essential metabolic pathway, bacteria would likely need to evolve several distinct resistance mechanisms simultaneously—a far more difficult evolutionary challenge than overcoming a single drug.
"Since evolution has already optimized this combination, we may be able to leverage it to develop novel antibiotic combinations," Blaskovich said.
Brendan Wren, a microbiologist at the London School of Hygiene & Tropical Medicine, noted that the work could also lead to the discovery of gene clusters that produce antibiotic compounds involved in other metabolic processes.
Brown also highlighted a broader implication: the way bacteria are typically tested for antibiotic susceptibility in laboratories—using nutrient-rich media—may systematically mask the activity of molecules targeting nutrient acquisition and synthesis systems. "For decades, drug discovery researchers have been screening for antibiotics under conditions that may actively mask this kind of activity," Brown said. "What this work tells us is that there is an entire world of nutrient-targeting molecules just waiting to be discovered."
The findings suggest that nutrient-targeting molecules represent a vast, largely untapped reservoir of potential antibiotics, with the team having catalogued dozens of known natural product antibiotics that similarly interfere with nutrient metabolism, to be detailed in a forthcoming review.