Bacteria genomes hold blueprints for anticancer drugs

Wednesday, 20 December, 2017

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Scientists at The Scripps Research Institute (TSRI), who previously discovered the prostate cancer-killing compound LNM E1, have now brought the family of LNM molecules even closer to clinical testing by ‘mining’ the information stored in bacteria genomes.

Published in the Proceedings of the National Academy of Sciences, their research suggests these hidden genes hold the blueprints for designing new, even more effective cancer-targeting compounds.

The leinamycin (LNM) family is a group of compounds called natural products, produced by a bacterium that lives in soil. The TSRI researchers were previously only aware of one member of the LNM family, a compound called LNM. By editing the genome of the bacterium, the scientists produced LNM E1, which they showed in 2015 could react with reactive oxygen species in prostate cancer cells, triggering death.

“So we knew the molecule was useful, but then what?” said Professor Ben Shen, lead investigator on the study. “We needed to make many variants to optimise efficacy in animal models.”

Unfortunately, synthesising LNM E1 to make analogues has proven challenging because of the compound’s complicated structure. The lack of analogues led Shen and his colleagues to look to nature for help. Luckily, Shen heads the Natural Products Library at TSRI’s Florida campus — a library consisting of purified natural products, partially pure fractions, crude extracts and bacterial strains collected from all over the globe that are available for screening.

By combing through this library and public datasets, the team discovered 49 bacteria with genes that appear to code for members of the LNM family. The researchers confirmed this finding through bioinformatics analysis and by isolating several of the newly discovered LNM compounds in the lab.

With this research, Shen and his colleagues now have an idea of the structural diversity in LNMs. They found that while bacteria evolved to have LNMs with many of the same characteristics, small changes, such as atomic differences in the building blocks of their core scaffolds, could make some LNMs more or less effective against cancer cells. The next step will be to study LNM molecule interactions with cancer cells to find out.

“This points the way toward a new therapeutic opportunity,” said Shen.

This finding represents a big shift in the discovery of natural product drug candidates, as, for a long time, scientists had to cast a wide net to discover potential medicinal compounds, more or less by chance, in animals, plants, bacteria and fungi. With the more focused, genome-driven technique employed at TSRI, scientists can close in on suspected sources of a potential drug more efficiently — in this case, mining bacteria genomes to find the instructions for making LNMs.

“The technological advances we’ve made enable us to quickly identify sources of these types of natural products,” said Shen. “This could dramatically impact the drug lead pipeline.”

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