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Scientists detect new natural products made by bacteria

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The waters are alive with life, from the world’s largest mammal – the blue whale – to microscopic bacteria. These bacteria are not only abundant, but they are also essential for maintaining the health of the entire eco- and climatic system.

There are photosynthetically active species, such as cyanobacteria, that produce approximately half of the oxygen in the atmosphere. Microorganisms also contribute to the fight against global warming by eliminating carbon dioxide from the atmosphere.

Despite this crucial significance, there has been limited research done on the variety of microorganisms found in the water. In order to better understand this diversity, a team of researchers led by Professor of Microbiome Research Shinichi Sunagawa is collaborating closely with Jörn Piel’s team. Both teams are at the ETH Zurich Institute of Microbiology.

To find new natural products produced by bacteria, Sunagawa and his team analyzed publicly accessible DNA data from 1,000 water samples collected at various depths from every ocean region on Earth. Ocean expeditions and out-at-sea observation platforms were some of the sources of the data.

Modern technologies such as environmental DNA (eDNA) analysis have made it simpler to look for new species and determine where known creatures are located.

But almost nothing is known about the special effects marine microorganisms have, or what chemical compounds they make that are important for how organisms interact with each other. In the best case, these compounds would also be good for people.

The research is based on the premise that the ocean microbiome contains untapped resources, such as natural compounds with antibacterial characteristics.

The extracted eDNA included in the samples was sequenced by the expeditions’ original researchers. The scientists were able to decipher the encoded information—the blueprints for proteins—by recreating complete genomes on computers. Finally, scientists combined this new data with the 8,500 marine microbe genome data sets already available to create a single database.

They were able to use these 35,000 genomes to search for novel microbial species, in particular for interesting gene clusters involved in biosynthesis (BGCs). A BGC is a collection of genes that creates a natural product’s synthesis pathway.

New species, molecules found

In this genome data, researchers found 40,000 BGCs that could be useful, as well as new species of bacteria in the phylum Eremiobacterota that had never been seen before. This particular bacterial community has previously only been found in terrestrial settings and lacked distinctive metabolic diversity.

Sunagawa and his team named this group of bacteria Eudoremicrobiaceae. They were also able to show that these bacteria are common and widespread. For example, Eudoremicrobium malaspinii, a member of this family, makes up to 6% of all bacteria in some parts of the ocean.

“The relatives in the ocean possess what for bacteria is a giant genome. Fully decrypting it was technically challenging because the organisms had not been cultivated before,” according to Sunagawa.

In addition, the newly discovered bacteria were shown to be a part of the microbial community with the highest BGC diversity among the samples analyzed.

He adds “as things stand, they are the most biosynthetically diverse family in the oceanic water column.”

The scientists took a close look at two Eudoremicrobiaceae BGCs. One was a gene cluster that, according to Sunagawa, has never before been discovered in this form in a bacterial BGC.

It contained the genetic code for a number of enzymes. The second case that was looked at was a bioactive natural substance that blocks a proteolytic enzyme.

Surprised by validation experiments

The researchers validated the structure and function of both natural compounds using studies in collaboration with the team led by Jörn Piel.

Since E. malaspinii could not be grown in a lab, Piel’s team had to put genes from a model bacterium into E. malaspinii so that the natural products could be made from them. Then, this bacterium created the corresponding compounds. The molecules were then separated from the cells, their structure was characterized, and the biological activity was verified.

In one instance, the enzyme activity predicted by computer programs did not match the outcomes of the trials, necessitating this action. Sunagawa asserts that “computer predictions for what chemical reactions an enzyme will trigger have their limitations.”

“This is why such predictions have to be validated in the lab if there’s any doubt.”

For a database of 40,000 potential natural compounds, doing so is an expensive and time-consuming endeavor that is simply not practical. However, Sunagawa notes that “our database has plenty to offer, and it’s accessible to all researchers who wish to use it.”

Sunagawa wants to look into unanswered questions about the evolution and ecology of microorganisms in the ocean, in addition to continuing to work with Piel’s group to find new natural products.

Since microorganisms can only passively spread over great distances, one of these is how they are dispersed in the water.

Additionally, he is interested in learning what advantages specific genes give bacteria in terms of ecology or evolution. Sunagawa believes the BGCs could have a significant impact.

Image Credit: HELENA KLEIN / ZHDK

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