Researchers identify a bacterium that produces a fully-fledged pharmaceutical weapon

For some years, active substance from ornamental plant leaves is viewed as a possible precursor to a new group of strong drugs. So far, however, it has been very laborious to produce in large quantities. That may change now: Researchers at the University of Bonn (Germany) have identified a bacterium that extracts the material and is easy to cultivate in the laboratory. The results are published in the journal Nature Communication.

The coralberry is now once again decorating many living rooms: In winter it bears bright red fruit, which makes it a popular ornamental plant at this time of year. For pharmacists, however, it is interesting for a different reason: It contains an active substance that has emerged in recent years as a shade of hope against asthma and certain types of cancer.

Unfortunately, getting the material with the cryptic name FR900359 (abbreviated: FR) in larger sizes is a bit laborious. Cultivation of plants in greenhouses takes several weeks; moreover, the output can vary greatly depending on the sample. Suddenly, they don’t take out the active ingredient themselves, but there are bacteria in their leaves that do it for them.

However, these only grow in the coral and cannot be cultivated in the laboratory. “

Dr. Max Crüsemann, Institute of Pharmaceutical Biology, University of Bonn

Complex collection line

FR manufacturing is a complex task. The bacteria have a specific collection line for this purpose, in which several enzymes work hand in hand. The bacterial genetic make-up specifies how this collection line needs to be established. “We have now studied large databases for other microorganisms that also have these genes for FR synthesis,” Crüsemann explains. “In the process, we came across another bacterium. Unlike its coralberry relative, it does not grow in plants, but in soil and is easily spread in culture media.”

This result should detect future FR production. However, it also allows for more detailed insights into how the active substance works. “We have known for several years that FR inhibits an important group of signaling molecules in cells, the Gq proteins,” explains Cornelia Hermes of the Institute of Pharmaceutical Biology. “That makes FR extremely effective: To date, no other fertilizer is known to inhibit Gq proteins with similar potency.”

Hermes continues her doctoral studies in the group Max Crüsemann and Professor Gabriele König and, together with her colleague Dr. René Richarz, was responsible for much of the now-published study. . One of the questions explored by the researchers was, why FR is such a defender. The molecule has two parts, the true heart and a side chain attached to it as an arm. Both are extracted separately and then bonded together. “The side chain is essential for FR action,” Crüsemann explains. “When it is absent or even slightly altered, the inhibitory effect on Gq proteins is greatly reduced.”

Central control station in the cell

The action of Gq proteins in the cell is similar to the function of a city emergency call center: They are the place where several signals from outside the cell come together. This activates them and then some metabolic processes are turned on or off. Instead of blocking several signaling pathways, so inhibition of the Gq protein is sufficient to achieve a therapeutic effect. This makes FR extremely effective, but also, if given to the whole body, is highly toxic.

“The goal is therefore to administer FR only to cells with pathologically modified behavior,” Crüsemann explains. Bacterial genes can be easily altered and distinguished today. “In this way, we can in principle generate FR changes with specific features, such as those that are transported directly to specific cells in the body and just do the work there,” says the bio- pharmacist.

The molecular history of FR is therefore likely to be expanded by another chapter as a result of the study: The active substance was discovered more than 30 years ago by Japanese researchers. In 2015, his method of biological action was defined by the research groups led by Professors Gabriele M. König and Evi Kostenis at the Institute of Pharmaceutical Biology. This work is now the basis for a research group of the German Research Foundation (DFG). Today, more and more research organizations around the world are exploring the potential of the molecule. With the newly discovered bacterium, they now have a new device.