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Disease and treatment

Researchers discover the secret behind a traditional Chinese medicine

Traditional Chinese medicine uses a plant called Aster tataricus (Taterinow’s aster) to cure infections. Now researchers have discovered that a newly identified fungus that lives inside the plant produces the substance with healing properties.

Some types of traditional Chinese medicine work well; others do not.

One medicine that may work well is derived from an extract of the plant Aster tataricus, which may have health-promoting properties and is traditionally used to fight infections such as those caused by staphylococci and Escherichia coli.

Nevertheless, Chinese medicine has not quite understood the plant’s secret.

New research shows that a newly identified fungus that lives inside the plant produces one of the substances that benefit health – not the plant itself.

The researchers behind a new study recently discovered the fungus and have investigated it thoroughly because the plant can make substances that may be useful in combating cancer.

“Some bioactive molecules in the fungus may have anti-cancer properties. Of course, we are very keen to discover more, but this means understanding how they are made,” explains the Danish contributor to the study, Tilmann Weber, Professor, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby.

The study was recently published in the Proceedings of the National Academy of Sciences of the United States of America.

Traditional Chinese medicine in stainless steel tanks

The researchers wanted to determine how the plant makes the bioactive molecules called astins.

Astins have long been known to be highly bioactive in animal studies.

They bind to an important human regulatory protein and thus can inhibit the immune response or potentially fight cancer.

The problem is that gathering enough Aster tataricus extract to conduct large-scale clinical trials with this potential drug candidate can take months, and producing commercial volumes with this method is even more problematic.

The plants grow slowly, and each plant contains only a small quantity of astin.

The alternative is to gather the plants in the wild, but this may threaten their existence.

Researchers would therefore prefer to isolate the biochemical production chain so that they can improve it in the laboratory or express it in a yeast or bacteria that is easier to grow in large stainless steel tanks.

“Developing a biotechnological process requires knowing which genes are involved and knowing about the biosynthesis pathway that leads to producing the desired substance. Astins have an exceptionally complex chemical structure,” explains the first author, Thomas Schafhauser, PhD, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Germany.

Fungus discovered inside Aster tataricus

However, the researchers dissected the plant to find both genes and signalling pathways and were surprised to find a fungus that lived inside the plant. They then separated the plant and fungus from one another, and the plant no longer produced the coveted astins. The fungus, which they named Cyanodermella asteris, produced them.

Cyanodermella asteris coexists symbiotically and probably beneficially with Aster tataricus. Nevertheless, the researchers managed to cultivate it in the laboratory.

They whole-genome sequenced it and identified the genes in the fungus that enable it to synthesize the astins.

“Fortunately, we had previously worked with similar enzymes used by Cyanodermella asteris to make astins. We compared their biochemical production pathways and identified how Cyanodermella asteris makes astins from very simple molecules, including amino acids such as proline, phenylalanine and serine. The fungus transforms them into more uncommon amino acids and then eventually uses these to produce the finished astins,” explains Tilmann Weber.

Plant and fungus make astins symbiotically

However, the researchers discovered something else surprising.

One type of astin has dichlorinated proline in the peptide chain – that is, a peptide with two chlorine groups attached to one of the amino acids – and is hydroxylated. This astin is called astin A.

However, the researchers could not find Cyanodermella asteris genes that could enable the entire biochemical construction of astin A.

Nor could they find this specific astin in the extract from the fungi cultivated in the laboratory – only in the extract from the plants.

“This very strongly indicates that the plants and fungi coexist symbiotically, with the fungus producing part of astin A and the plant completing the process. But perhaps astin A cannot be produced unless the plant sends the fungus a signal to produce it. This is very exciting scientifically, and we would like to determine what the missing enzyme is, because this may be useful in biosynthesis in the laboratory,” says Tilmann Weber.

Tilmann Weber and his colleagues speculate that the plant and fungus cooperate because astin A could repel insects or parasitic fungi that may threaten Aster tataricus.

A potentially valuable discovery

Tillman Weber explains that studies like this generally lay the foundation for new knowledge about the methods nature has developed to make various molecules.

This knowledge may be valuable later when researchers find other molecules that can become excellent medicines when slightly modified.

These slight modifications might be obtained by enzymes from either Cyanodermella asteris or Aster tataricus.

“Unfortunately, I am not participating in the next phase of the project, but I know my colleagues plan to continue investigating astins to determine whether they have any of the properties we hope they have,” says Tilmann Weber.

Antitumor astins originate from the fungal endophyte Cyanodermella asteris living within the medicinal plant Aster tataricus” has been published in the Proceedings of the National Academy of Sciences of the United States of America. In 2017, the Novo Nordisk Foundation awarded a Challenge Programme grant to Tilmann Weber for the project Integration of Informatics and Metabolic Engineering for the Discovery of Novel Antibiotics (IIMENA).

Tilmann Weber
Senior Researcher
We need new antibiotics. It’s as simple as that. Many disease-causing bacteria no longer respond to existing antibiotics. But actually, there is not much work being done in this area. Today, only few pharmaceutical companies are actively working in developing truly novel antibiotics and not only variants of existing drugs. The development pipelines are almost empty, because the payoff has been too low for many years and continues. But the problem is that our current antibiotics are quickly becoming ineffective, leaving patients at risk of dying from even simple infections. So, we need to find new antibiotics now – and we need to optimize the ways, we can find them. Until now, researchers looking for new antibiotics would often try to grow soil bacteria and assess if any of them could kill disease-causing bacteria. Afterwards, they would isolate the antimicrobial compound. But in this program, the approach is quite different and very new. We are using laboratory evolution to induce antibiotics production. This means, that they grow different microbes together in order to see if they start fighting each other.