From Rare Soil Microbe, a new antibiotic candidate for drug-resistant infections

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Scientists have discovered a potential candidate for antibiotic development in a soil bacterium known as Lentzea flaviverrucosa.

As drug-resistant and emerging infections become an increasingly serious threat to global health, the demand for new types of antibiotics is increasing. Researchers are racing to reexamine a group of microbes known as actinomycetes, which are one of our most effective therapeutic sources.

Scientists from Washington University in St. Louis and the University of Hawaii have discovered a potential candidate for developing antibiotics from one of these microbes, the soil bacterium known as Lentzea flaviverrucosa. They reported their findings in a study published the week of April 11 in the journal Proceedings of the National Academy of Sciences.

“Rare actinomycetes are an underexploited source of new bioactive compounds,” said Joshua Blodgett, assistant professor of biology in arts and sciences, co-corresponding author of the new study. “Our genomics-based approach allowed us to identify an unusual peptide for future drug design efforts.”

Joshua Blodgett

Joshua Blodgett, assistant professor of biology, Washington University in St. Louis. Credit: Sean Garcia, University of Washington

Actinomycetes produce bioactive compounds that form the basis of many clinically useful drugs, especially antibiotics and anti-cancer agents. Since the 1940s, pharmaceutical companies have analyzed many common actinomycetes to see what they might produce. Today, about two-thirds of all antibiotics used in hospitals and clinics come in part from actinomycetes.

But some of these microbes – known as rare actinomycetes – have been cataloged but have not been studied extensively until now.

The definition of “rare” isn’t set in stone, but these actinomycetes tend to be harder to find in nature than others, and they can grow more slowly, Blodgett said. For these and other reasons, many rare actinomycetes have not been fully characterized for drug discovery and biotechnology purposes.

Among the rare actinomycetes, Lentzea flaviverrucosa emerged as a star, Blodgett said.

“It has unusual biology, coding for unusual enzymology, resulting in the production of unexpected chemistry, all hosted in a largely overlooked group of bacteria,” he said.

Blodgett and collaborators, including co-corresponding author Shugeng Cao from the University of Hawaii, found that this rare actinomycete produces molecules active against certain types of human ovarian cancer, fibrosarcoma, prostate and leukemia cell lines.

Scientists first spotted Lentzea flaviverrucosa when they went in search of rare actinomycetes with a genetic mark indicating that they can make piperazyl molecules. These molecules incorporate an unusual building block that is an indicator of potential drug-like activities, Blodgett said.

But as the researchers dug deeper, they discovered a few other surprises.

“At a high level, it looked like one region of the genome might be able to make two different molecules. It’s just a little weird,” Blodgett said. “Usually we think of a cluster of genes, clusters of genes that are like blueprints for making individual drug-like molecules. But it seemed like there was almost too much predicted chemistry in that single cluster.

The first clues turned out to be correct. Using a combination of modern metabolomics with chemical and structural biology techniques, Blodgett and his team were able to show that this rare actinomycete actually produces two different bioactive molecules from a single set of genes called a supercluster.

Superclusters are rare in biology. This particular type of supercluster codes for two different molecules which are then welded together in an atypical chemical reaction.

“Nature welds two different things together,” Blodgett said. “And, ultimately, against several different cancer cell lines, when you glue A and B together, it turns into something more potent.”

Reference: “Discovery of unusual dimeric piperazyl cyclopeptides encoded by biosynthetic supercluster DSM 44664” April 11, 2022, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2117941119

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