Antibiotic resistance has loomed over humans since the moment we started using antibiotics. In the 20th century, the drugs downgraded potentially life-threatening bacterial infections to mere inconveniences—a miracle of modern medicine, it seemed. But the drugs aren’t really a human invention; we mostly swiped them from microbes, which have been locked in an arms race with each other for centuries. Microbial evolution has crafted both deadly molecules and clever tricks to dodge death as the wee organisms endlessly battle over turf and resources. More than 80 percent of the antibiotics used in clinics today are based on those turf-war weapons, which scientists refer to as “natural products.”
For decades, humans mined antibiotic molecules from microbes and tweaked them to develop new drugs, staying ahead of evolution’s cunning countermeasures. But in recent times, new natural products have been harder to find, and the pipeline of new antibiotics has slowed to a trickle. Meanwhile, existing antibiotics have been overused, and resistance has mounted to critical levels. Most antibiotics are single bioactive molecules, and some can be thwarted with single mutations. While the current situation is dire, a study in Nature this week reports a compelling discovery that not only points to a potentially new antibiotic regimen, but also an entirely new strategy to once again get ahead in the microbial arms race.
Exciting find
The study, led by biomedical researcher Eric Brown at McMaster University in Ontario, Canada, reports the discovery of a large block of genes—dubbed a “megacluster”—that codes for four molecules that appear to work in concert to derail a single essential metabolic pathway.
It’s “an exciting advance in efforts to restock the antibiotic arsenal,” Steven Rutherford, a microbial sciences expert at Genentech, wrote in an accompanying commentary piece in Nature. “More broadly, the study provides a road map showing how genome mining can be used to identify new antibacterial natural products and strategies for using them.”
The pathway the megacluster’s products attack is one for making biotin, also known as vitamin B7. The nutrient is required for growth and virulence in many human pathogens, and, more specifically, it’s a cofactor that critical metabolic enzymes need to work properly. Some bacteria can scavenge biotin from their surroundings, but it’s generally scarce, and bacteria contain evolutionarily conserved pathways to make it themselves.
Brown and his colleagues interestingly found the biotin-targeting megacluster in Streptomyces species, which are very well studied. Streptomyces are bacteria that live in soil and are known as gold mines for antibiotic molecule discovery. Many natural products have already been extracted from them, including the antibiotic streptomycin, an essential medicine discovered in the 1940s. Despite this, the megacluster has been overlooked until now, possibly in part because bacteria in labs are often grown in nutrient-rich media.
Fresh strategy
Also, when researchers are looking for new antibiotics in bacterial genomes, they scan for biosynthetic gene clusters (BGCs) that could be responsible for producing single molecules. But Brown’s team identified a cluster of four clusters—the megacluster—that produces not just one, but four molecules that work in different ways to trip up the biotin pathway. Careful study revealed that three of the clusters produce antibiotics molecules—stravidins, acidomycins, dapamycins—that each thwart a different enzyme in the biotin biosynthesis pathway. The remaining fourth cluster produces 2-methyl-7-keto-8-aminopelargonic acid, or α-Me-KAPA, which appears to be a dummy molecule that takes the place of a biotin precursor, basically hijacking the pathway to yield a useless biotin lookalike.
Further, the megacluster is flanked on both sides for the code to make streptavidin, a protein known to take up and sequester biotin.
In all, the megacluster provides a sophisticated siege on an essential pathway in many bacteria, including Streptomyces’ foes. Experiments in test tubes and in mice confirmed that the megacluster’s products could kill off various bacteria and were more potent when used in combination.
As antibiotic resistance has increased in clinics, doctors and researchers have had to test which combinations of drugs might be able to boost efficacy. But, as Rutherford noted in his commentary, “The discovery of a natural megacluster that encodes the production of synergistic biotin-synthesis inhibitors suggests that evolution has already identified effective combinations of antibacterials that act through distinct mechanisms.” Moreover, such evolved synergistic systems may be harder for microbes to develop countermeasures against, thus they may stave off resistance.
Rutherford is careful to note that there are many big steps between this discovery and having a new antibiotic regimen in clinics. That includes more basic research, optimization of the molecules for delivery in humans, as well as pricy and lengthy safety and efficacy clinical trials.
Still, moving from scanning for individual BGCs to “megaclusters” is a fresh strategy that could reinvigorate natural product development.
“The architecture of the anti-biotin megacluster provides a paradigm for naturally evolved combination therapies, supporting a shift in antibiotic discovery from isolating individual hits to reconstructing native synergistic systems,” Brown and his colleagues conclude. “As genome-mining methods advance, the identification of similar megaclusters may reveal new paths for overcoming antimicrobial resistance by mimicking the strategies of nature.”
