Nav: Home

Pharmaceuticals from a coal mine?

February 06, 2017

Digging around in the dark can sometimes lead to interesting results: in the acidic waters of an abandoned coal mine in Kentucky (USA), researchers discovered ten previously unknown microbial natural products from a strain of Streptomyces. They have now introduced these compounds in the journal Angewandte Chemie. Four of the molecules contain a cyclopentenone ring, which is rare in this class of substances.

The team led by Khaled A. Shaaban and Jon S. Thorson at the University of Kentucky (UK)'s Center for Pharmaceutical Research and Innovation (Lexington, USA) is part of a broader new initiative focused on mining-associated environments in Appalachian Kentucky. The goal is to seek out new organisms that produce previously unknown metabolites that could be potential starting materials for pharmaceutical development.

The team has discovered previously unknown metabolites of a strain of Streptomyces in the abandoned underground Rock Creek coal mine in McCreary County. These compounds belong to the family of ansamycins, compounds that contain an aromatic ring system bridged by a long, aliphatic chain. The geldanamycins (Gdm) are a subset of the ansamycins whose aromatic ring consists of a quinone group, a six-membered ring of carbons with two double bonds and two oxygen atoms attached by double bonds. Gdm inhibits heat shock protein 90 (Hsp 90), a protein important for cell survival. Various Gdm analogs are in clinical use as antitumor drugs.

Characterization of the new compounds revealed that six of them are previously unknown geldanamycin variants. Four others are a new type of ansamycin: Instead of an aromatic ring, they have a cyclopentenone group, a ring of five carbons with a double bond and one oxygen atom bound by a double bond. These new compounds were named McCrearamycins after their county of origin.

The researchers speculate that Gdms could be precursors of the McCrearamycins. Experiments with Gdms and model substances revealed that the quinone group can easily be converted to a cyclopentenone via a benzylic acid rearrangement. This could be a new synthetic route for the production of cyclopentenone derivatives.

Along with three known Gdm derivatives, the new compounds were tested for their ability to inhibit Hsp 90 and to probe their cytotoxicity against a line of cancer cells. The two did not correlate in all cases. It is clear that small structural variations can give rise to differences in cell uptake and/or different cytotoxicity mechanisms. This is worth examining further in the development of new pharmaceuticals.

In collaboration with S. Randal Voss and UK's Ambystoma Genetic Stock Center, researchers also validated a new test for the activity of Hsp 90. The Mexican axolotl (Ambystoma mexicanum) is able to regenerate damaged limbs. Hsp 90 plays an important role in this process. In the presence of massive doses of Gdm, the amputated tails of axolotl embryos were not able to regenerate. High doses also caused developmental abnormalities. Gdm is thus useful for investigating the role of Hsp 90 in regeneration processes, and the test is useful in the search for Hsp 90 modulators.
About the Author

Dr. Jon Thorson is Professor of Pharmaceutical Sciences in the University of Kentucky (UK) College of Pharmacy and Director of the UK Center for Pharmaceutical Research and Innovation. His main specialty is biocatalyst and natural product-based lead discovery. Dr. Thorson also serves as the co-Director of UK's Markey Cancer Center's Drug Discovery, Delivery and Translational Therapeutics Program and co-Director of the Drug Discovery and Development Core in the UK Center for Clinical and Translational Science.


Related Streptomyces Articles:

Genome mining reveals novel production pathway for promising malaria treatment
Researchers at the Carl R. Woese Institute for Genomic Biology at the University of Illinois are exploring the relationship between microbial natural products and the gene clusters that enable their production.
Bacteria on tumors influences immune response and survival of patients with pancreatic cancer
MD Anderson researchers find tumor microbiome influences immune response and patient survival in pancreatic cancer.
Compound that kills drug-resistant fungi is isolated from ant microbiota
A project conducted by researchers in Brazil and the US investigated bacteria living in symbiosis with insects as a source for novel drugs.
Time-lapse microscopy helps reveal brake mechanism in Streptomyces lifecycle
Streptomyces are soil-dwelling bacteria that produce approximately two-thirds of the antibiotics in current clinical use.
Microbes hitched to insects provide a rich source of new antibiotics
In an exhaustive search of microbes from more than 1,400 insects collected from diverse environments across North and South America, a UW-Madison research team found that insect-borne microbes often outperformed soil bacteria in stopping some of the most common and dangerous antibiotic-resistant pathogens.
More Streptomyces News and Streptomyces Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...