Landmark study reveals ‘megacluster’ of bacterial genes behind arsenal of potent antibiotics

Researchers at McMaster University have discovered what they describe as a “megacluster” of genes in Streptomyces bacteria that produces four antibiotics that work together to stop rival bacteria.  

Published in Nature, the new study describes an unusual stretch of DNA that encodes four distinct families of natural product antibiotics, including one compound entirely new to science and another that had never before been recognized as an antibiotic. Together, the four molecules work to target a single vulnerability: biotin, an essential nutrient required by most bacteria for survival. 

Siege strategy

Also called vitamin B7, biotin plays a critical role in bacterial growth and cell division. The newly characterized antibiotics disrupt biotin production, uptake, and use, offering a striking new model for how antibiotics can work together — and a promising strategy in the fight against drug-resistant infections. 

Eric Brown, a professor of biochemistry and biomedical sciences at McMaster and principal investigator on the new study, likens the approach to a siege.  

“It’s really sinister,” he says. “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.”  

That four distinct families of antibiotics all work together to attack the same area in different ways is unique in its own right; but that all four are enabled by genes that are co-located is “unheard of,” according to Brown, a member of the Michael G. DeGroote Institute for Infectious Disease Research.  

Flanking genes

What’s more, Brown’s team discovered that the four antibiotic-making gene clusters are also flanked by two streptavidin genes, which allow the bacteria to manufacture proteins that bind biotin. As such, the researchers argue that it’s no coincidence that these four gene clusters are positioned side-by-side-by-side-by-side in the Streptomyces genome. 

“It’s very intentional design,” says Brown, an executive member of NexusHealth at McMaster. “The proteins are made to bind up available biotin, while their neighbouring antibiotics prevent competing cells from getting to it first.” 

Importantly, the study found that the anti-biotin antibiotic megacluster is widespread across different species of Streptomyces, suggesting that the strategy evolved long ago and has been conserved over millions of years.  

“It’s not only a very complex and ingenious architecture, but it’s also incredibly abundant,” explains Rodion Gordzevich, a postdoctoral fellow in Brown’s lab. “Our analysis showed that this megacluster is even more widespread across Streptomyces genomes than the genes responsible for making streptomycin — one of the classic antibiotics discovered from these bacteria back in the 1940s.”  

Therapeutic potential

Brown’s team also tested the newly characterized compounds in animal models of infection and found that two of them were highly effective against multidrug-resistant E. coli, offering an early indication that the strategy could have real therapeutic potential. 

The landmark discovery, which was made in collaboration with Professor Gerry Wright’s lab at McMaster, arrives at a time when researchers across the world are urgently searching for new antimicrobial strategies to combat the rise of multidrug-resistant infections.  

Brown believes that, should it eventually be adopted in clinics, a coordinated strategy like the one used by Streptomyces could theoretically make it harder for resistance to develop, since bacteria would likely have to evolve several distinct resistance mechanisms to protect against it.  

New approaches

Brown’s lab has long been interested in the synthesis of nutrients — like biotin — as a target for new antibiotics, arguing that the way bacteria are studied in laboratories can mask molecules like these biotin-targeting drug candidates.   

“The dominant — in fact, accredited — method for determining whether or not a bacterium is susceptible to an antibiotic is to test it in microbiological media, which is incredibly rich in vitamins, amino acids, trace metals, and other nutrients,” explains Brown. “There is no reasonable way to know whether molecules that target these nutrient acquisition and synthesis systems are actually working when the nutrients themselves are so overwhelmingly abundant in lab conditions.” 

Next steps

Gordzevich, who co-first authored the new study with former Wright Lab postdoctoral fellow Min Xu, says the Brown Lab’s novel approach to drug discovery has allowed the team to scour the scientific literature for other known molecules that may unknowingly target nutrient synthesis.   

In doing so, they recently catalogued dozens of known natural product antibiotics that similarly interfere with nutrient metabolism, the details of which will be published in a forthcoming review. 

Taken together, the findings suggest that nutrient-targeting molecules are a vast reservoir of potential antibiotics that are “hiding in plain sight,” says Brown.  

“For decades, drug discovery researchers have been screening for antibiotics under conditions that may actively mask this kind of activity,” says Brown. “What this work tells us is that there is an entire world of nutrient-targeting molecules just waiting to be discovered.”