Some of the most important drugs in medicine were not designed by a chemist — they were made by microbes. Many antibiotics, immunosuppressants, cholesterol-lowering medications, and anticancer agents are derived from “specialized metabolites,” compounds that bacteria and fungi produce to defend themselves in the wild.
But of the millions of microbial species that exist across the planet, only a small handful are prolific chemists. In fact, roughly three-quarters of our antibiotics come from a single type of bacteria, while most other microbes make almost none.
In a new study out of McMaster University, researchers have identified a biological pattern that helps explain why only some microbes are chemistry powerhouses, and the reason could help guide the search for urgently needed new medicines.
Published today in Nature Microbiology, the study showed that — compared to their single-celled counterparts — microbes that have evolved multicellular lifestyles are especially rich sources of the natural compounds that underpin many antibiotics and other drugs.
The new findings are a neon sign for drug discovery researchers, drawing their attention directly toward the types of bacteria and fungi that are most likely to harbor undiscovered medicinal compounds.
“This paper addresses a foundational question with direct bearing on the discovery of antibiotics and other medicines,” says Cameron Currie, a professor of biochemistry and biomedical sciences at McMaster and a member of the Michael G. DeGroote Institute for Infectious Disease Research (IIDR). “We hypothesized that organisms that are multicellular might possess an expanded capacity for producing important chemistry — and it turns out that there is a clear and indisputable link there.”
Currie, who co-led the new study with Associate Professor Lindsay Kalan, says that their hypothesis was rooted in the fact that some of the most medicinally significant organisms have evolved multicellular lifestyles. For instance, the fungus Penicillium, which produces penicillin antibiotics, and the bacterium Streptomyces, which produces several clinically approved medicines, are both multicellular.
That raised for Currie and Kalan an intriguing question: is this a coincidence or a pattern?
To find out, the research team — driven in large part by Rauf Salamzade, a PhD candidate in Kalan’s lab — used a suite of computational tools, including some developed here at McMaster, to explore the genetic codes of thousands of different microbes, looking for specific clusters of genes that are known to enable antibiotic production.
The findings were striking: the vast majority of organisms under study had only a limited capacity to produce these specialized chemicals; however, a select few stood out as exceptions. These included multicellular groups such as cyanobacteria, myxobacteria, and actinomycetes, each of which contained disproportionately large numbers of the gene clusters associated with antimicrobial production.
Multicellular Actinomycete bacteria growing in a connected network of filaments (left) juxtaposed against the single-celled bacteria Pseudomonas aeruginosa (right).
The researchers then traced the evolution of these lineages through time and found that increases in chemical-producing capacity consistently coincided with the emergence of multicellularity.
Both Kalan and Currie believe that a multicellular lifestyle offers several advantages for microorganisms, and that the ability to produce complex chemistry is among them.
“Producing antibiotics and other specialized compounds at ecologically relevant scales requires a significant amount of energy,” explains Currie, the Stephen A. Jarislowsky Chair in Pandemic Research. “For single-celled organisms, maintaining the genetic machinery needed to make these diverse chemicals may not be worth the energy investment. On the other hand, for microbes that adopt multicellular lifestyles, different cells can share energetically expensive tasks, and can therefore collectively absorb the costs of producing these complex chemicals.”
Importantly, Kalan, the Canada Research Chair in Skin Microbiome and Infectious Disease, notes that there are several groups of multicellular microbes that have received little attention in drug discovery to date, suggesting that these organisms may be an untapped reservoir of new medicines, including antibiotics that could help fight drug-resistant infections.
“These findings allow us to be more thoughtful and pointed in our research efforts,” says Kalan, the associate director of the IIDR. “Already, most of the antimicrobials used in the clinic are derived from these multicellular organisms. Now that we know that’s not a coincidence, we can take a more targeted approach to searching for new medicines.”
Beyond its implications for drug discovery, the findings provide new insight into the origins of multicellular life. The researchers suggest that the ability to produce increasingly sophisticated chemical compounds may have been a key advantage that favoured the emergence of cooperative, multicellular organisms.
This research was supported by funding from the National Institutes of Health, the Stephen A. Jarislowsky Foundation, and the Canadian Institute for Advanced Research.