Researchers are seeking out potential new therapeutics as drug-resistant and emerging infections are becoming an increasingly serious global health threat. Now, researchers at the Washington University in St. Louis and the University of Hawaii report they have discovered a potential candidate for drug development from the soil bacterium known as Lentzea flaviverrucosa.
The findings are published in the journal Proceedings of the National Academy of Sciences in a paper titled, “Discovery of unusual dimeric piperazyl cyclopeptides encoded by a DSM 44664 biosynthetic supercluster.”
“Rare actinomycetes are an underexploited source of new bioactive compounds,” explained Joshua Blodgett, PhD, assistant professor of biology in arts & sciences and co-corresponding author of the new study. “Our genomics-based approach allowed us to identify an unusual peptide for future drug design efforts.”
“It has unusual biology, encoding for unusual enzymology, driving the production of unexpected chemistry, all harbored within a largely overlooked group of bacteria,” he said.
The collaborators discovered that this rare actinomycete produces molecules that are active against certain types of human ovarian cancer, fibrosarcoma, prostate cancer, and leukemia cell lines.
The scientists initially spotted L. flaviverrucosa when they went looking for rare actinomycetes with a genetic hallmark that indicates that they can make piperazyl molecules. These molecules incorporate an unusual building block that is a flag for potential drug-like activities, Blodgett said.
“At a high level, it looked as if one region of the genome might be able to make two different molecules. That’s just a little strange,” Blodgett said. “Usually we think of a gene cluster, groups of genes that are like blueprints for making individual drug-like molecules. But it looked like there was almost too much chemistry predicted within this single cluster.”
Using a combination of modern metabolomics with chemical and structural biology techniques, the researchers were able to demonstrate that this rare actinomycete actually produces two different bioactive molecules from a single set of genes called a supercluster.
“Nature is welding two different things together,” Blodgett said. “And, as it turns out, against several different cancer cell lines, when you stick A and B together, it turns into something more potent.”