This ‘supercluster’ of a rare soil microbe could produce amazing new drugs

The search for potentially potent new therapeutic molecules in nature is a vital quest driven by parallel health crises: antibacterial resistance and the growing global cancer burden.

Now, a team of scientists has discovered that a rare soil microbe produces peculiar but familiar molecular “building blocks” with drug-like activity. This could be a boon for drug design and discovery programs.

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

Their exploration focused on a group of soil-dwelling spindly bacteria called actinomycetes, which, fortunately for us, are prolific producers of medicinal compounds.

“Once considered largely devoid of new drugs, [genome sequencing] have revealed a wealth of yet unknown drug-like molecules hidden in the genomes of actinobacteria,” the team wrote in their paper, led by pharmacologist Chunshun Lia from the University of Hawaii.

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

A resurgence of interest in exploring actinomycetes as rich sources of bioactive molecules has been fueled by the global health threat of antimicrobial resistance, which breeds drug-resistant infections faster than new drugs can be. products. Superbug infections are now the third leading cause of death worldwide, according to a sobering analysis earlier this year.

So, in the search for new drug candidates, Blodgett, Lia and their colleagues turned their attention and their genome sequencing tools to a particularly rare actinomycete, which has been found in soils in China and goes by the name of Lentzea flaviverrucosa.

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

“It has an unusual biology, coding for unusual enzymology, resulting in the production of unexpected chemistry, all hosted in a largely overlooked group of bacteria,” says Blodgett of L. flaviverrucosa.

The team’s first attempts to scan the genomes of rare actinomycetes had suggested L. flaviverrucosa could make a few small circular molecules called piperazyl molecules, which are known to serve as useful scaffolds for drug synthesis.

Using a battery of techniques, the researchers found that L. flaviverrucosa actually produces two types of piperazyl molecules. But these new compounds were different, produced by a single set of genes called a supercluster.

“At a high level, it looked like one region of the genome might be able to make two different molecules,” says Blodgett.

“Usually we think of a cluster of genes [as] groups of genes that are like blueprints for making individual drug molecules. But it seemed like there was almost too much predicted chemistry in that single cluster.”

Once the researchers solved the molecular structures of the two particular compounds, they soon realized that one of them was quite different from those previously described. It consisted of two hexagonal molecules joined together to form an unbalanced and asymmetrical duo, which had potential drug activity when tested against certain types of human cancer cell lines.

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

Of course, we shouldn’t forget that testing drugs on lab-grown cell lines is a world away from treatments showing therapeutic benefits in clinical trials. Moreover, it takes decades for potential drug candidates to move from the lab to testing and the clinic, and many fail in the process.

“Much more work, focus and funding is needed for new approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance,” Ursula Theuretzbacher, independent expert in antibacterial drugs, and her colleagues wrote in 2019.

Still, the hope is that with more analyzes like this, which seek to identify the most promising bacterial strains and the compounds most likely to succeed, researchers are on the right track, without wasting time.

The research has been published in PNAS (link not yet active at time of writing).

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