Many of the medicines we use today originate in nature. Penicillin is a classic example: a substance discovered in a fungus that has since saved millions of lives. But nature’s compounds are not always perfect. Despite their beneficial properties, some are initially too toxic to be used in humans.

“Nature is incredibly generous in providing compounds that we can actually use directly as medicines. However, the reality is often that some kind of chemical modification is needed before they become usable,” explains Professor Thomas Poulsen from the Department of Chemistry at Aarhus University.

In the ERC-funded project RECYPION, Thomas Poulsen’s research team has developed a new method in which some of nature’s most complex compounds are built from the ground up - like LEGO bricks. The method makes it possible to modify small parts of the molecules and thereby create entirely new variants that nature itself cannot produce.

The method has been published in the top journal Journal of the American Chemical Society.

“We can make exactly the same compounds as nature, but we use a fundamentally different approach. Because we do it this way, we can also vary the structure. Nature cannot,” he says.

The researchers call this type of compound “super natural products.” Super natural compounds. Not in the sense of being supernatural, but beyond nature - substances inspired by nature and refined through human ingenuity.

A central goal of RECYPION is to identify new antibiotics capable of fighting bacteria that have become resistant to the treatments we use today. Antibiotic resistance is a growing global challenge, and the need for new solutions is urgent.

“There are certain types of microorganisms for which we no longer have anything that works. It’s truly critical. The world before the development of antibiotics is not a place we want to return to in any way,” says Thomas Poulsen.

The compounds the team is working with have shown effectiveness against bacteria and infectious diseases. They are also difficult for bacteria to develop resistance to. But there is a downside: the compounds can be toxic to human cells. The researchers are therefore trying to design new versions that are more gentle.

“The resistance challenges and the lack of completely new types of antibiotics mean that we now have to consider known compounds that are initially too toxic. But then we of course have to find ways to eliminate the toxic effects,” says Thomas Poulsen.

The research has already resulted in a new method for producing the complex antibiotic lasalocid acid in just 11 steps - previously, the synthesis required more than 30 steps.

This is a major breakthrough that makes it possible both to test new variations and to produce the compounds in quantities needed for further development.

“If you need 30–40 synthetic operations to build a compound, it will never become a product. It must be efficient if it is to be scaled up and used in the real world,” he says.

For Thomas Poulsen, the work is not only about improving existing compounds but also about challenging our ideas of what is possible.

“There’s a reason nature has spent billions of years refining specific structures. They have unique properties, and they challenge us to develop entirely new ways of building molecules,” he says, adding:

“Furthermore, we can try to combine nature’s inspiration with our own creativity and thereby create entirely new classes of compounds that still carry elements of nature. Hopefully, such ‘hybrid compounds’ can help find solutions for the diseases for which we still lack effective treatments.”

ERC is the European top research programme. In addition to an ERC Consolidator Grant, Thomas Poulsen has also received an ERC Proof of Concept Grant to explore the innovation potential of a class of natural compounds with immunosuppressive effects.

This article is translated with the help of CoPilot.

Additional information
We strive to ensure that all our articles live up to the Danish universities' principles for good research communication(scroll down to find the English version on the web-site). Because of this the article will be supplemented with the following information:
Funding	The research is funded by the European Research Council
Conflicts of interest	None
Read more	Modular Total Synthesis of Lasalocid Acid A through Direct C(sp3)–C(sp3) Attached Ring Construction
Contact	Thomas Poulsen Professor Department of Chemistry, Aarhus University Phone: +45 61 14 18 44 Email: thpou@chem.au.dk