‘Supercluster’ of rare soil microbe could provide amazing new drugs

(ORDO NEWS) — The search for new and potentially powerful therapeutic molecules in nature is a vital quest, spurred on by parallel health crises: antibacterial resistance and the growing global burden of cancer.

Now, a team of scientists has discovered that a rare soil microbe produces unusual but familiar molecular building blocks with drug activity. This can be a good support for drug development and discovery programs.

“Our genomics-based approach allowed us to identify an unusual peptide for future drug development efforts,” says Joshua Blodgett, a microbiologist at Washington University in St. Louis and senior author of the new study.

The researchers’ focus has been on a group of spindle-shaped, soil-dwelling bacteria called actinomycetes, which, fortunately for us, are prolific producers of drug compounds.

“It was once thought that there were no new drugs in this group, but [genome sequencing] technologies have uncovered a deep well of undiscovered drug molecules hidden in the genomes of actinobacteria,” the group, led by pharmacologist Chunshun Lia of the University of Hawaii, writes in their paper.

In actinomycetes, scientists have found the building blocks for more than 50 percent of the antibiotics used in clinics and hospitals today, including the first active agent against tuberculosis, as well as many anti-cancer drugs and immunosuppressants.

A resurgence of interest in the study of actinomycetes as rich sources of biologically active molecules has been sparked by the global health threat of antimicrobial resistance, which is generating drug-resistant infections faster than new drugs are available.

According to a sobering analysis earlier this year, “superbug” infections have become the third leading cause of death worldwide.

So in their search for new drugs, Blodgett, Lia and their colleagues turned their attention and genome sequencing tools to one particularly rare actinomycete found in the soil of China called Lentzea flaviverrucosa.

Because L. flaviverrucosa is harder to find in nature than other actinomycetes and harder to grow in the laboratory, it has not been studied as much as its more common drug-producing relatives. And what the researchers found was pretty strange.

“It has an unusual biology, coding for an unusual enzymology, producing unexpected chemicals, all hidden in a group of bacteria that few people know about,” Blodgett says of L. flaviverrucosa.

The team’s previous attempts to scan the genomes of rare actinomycetes suggested that L. flaviverrucosa could produce several small, round molecules called piperazil molecules, which are known to serve as useful scaffolds for drug synthesis.

Using a range of methods, the researchers found that L. flaviverrucosa does indeed produce two types of piperazil molecules. But these newly invented compounds were different and produced by a single set of genes called a supercluster.

“At a high level, it seemed like one region of the genome could produce two different molecules,” says Blodgett.

“Usually we think of a gene cluster [as] groups of genes that are like blueprints for making individual drug-like molecules. But there seems to be too much chemistry predicted in this cluster.”

When the researchers determined the molecular structure of the two unusual compounds, they also soon realized that one of them was completely different from any previously described.

It consisted of two hexagonal molecules joined together to form a one-sided, asymmetric duo that had potential drug activity when tested against certain types of human cancer cell lines.

“Nature welds two different things together,” explains Blodgett. “And it turns out, against several different cancer cell lines, when you put A and B together, you get something more powerful.”

Of course, we should not forget that testing drugs on laboratory-grown cell lines is still far from a treatment that demonstrates a therapeutic effect in clinical trials. In addition, it takes decades for potential drug candidates to go from the lab, through trials, to the clinic, and many of them fail in the process.

“Much more work, attention and funding is required for new approaches to lead to the development of effective antibacterial drugs for the sustainable fight against antibacterial resistance,” Ursula Theuretzbacher, an independent expert on antibacterial drugs, and her colleagues wrote in 2019.

However, there is hope that with more analyzes like this one that seek to determine which bacterial strains are the most promising and which compounds have the best chance of success, researchers are on the right track without wasting time.

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