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New study: natural antibiotic as cancer therapy?


Natural product Carolacton inhibits the growth of cancer cells

Many diseases can be successfully treated with natural active ingredients. A natural product could also significantly improve therapy for cancer in the future. The results of a current study suggest that the natural active ingredient Carolacton or derived active ingredients could be used to inhibit cancer cell growth.

In a recent study, scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Center for Infection Research (HZI) examined the effects of the natural product Carolacton and discovered a key enzyme in folic acid metabolism as a target for the active ingredient. This opens up the possibility of also inhibiting the growth of cancer cells with the help of Carolacton, the researchers report. The results of her study were published in the specialist journal "Nature Communications".

Natural active ingredient formed by microorganisms

Carolacton is formed as a natural active ingredient by microorganisms living in the soil and has antibiotic properties, report the study authors. Carolacton belongs to the class of polyketides and is isolated from the Myxobacterium Sorangium cellulosum. In principle, however, the active ingredient cannot be used as an antibiotic in humans, since it inhibits a key enzyme of folic acid metabolism and the latter has a key function in most living things - including humans.

Antibiotic effects of Carolacton

"Carolacton can interfere with important processes in bacteria and thus also reduce the biofilm formation of Streptococcus mutans, the main cause of dental caries," emphasizes Professor Rolf Müller, head of the "Microbial Natural Products" department and managing director at HIPS. At the same time, Carolacton forms a growth inhibitor of Streptococcus pneumonieae, one of the most life-threatening microorganisms. In view of the effect on the folic acid metabolism, which is essential for growth, since, for example, DNA building blocks are made from it, Carolacton is hardly usable as an antibiotic. However, the target enzyme is increasingly needed by fast-growing cancer cells, and their growth can be slowed down by Carolacton, the scientists report.

Key enzyme for binding the active ingredient identified

The researchers were particularly interested in the antibiotic activities and the antibiofilm activity of the natural active ingredient. The goal was a better understanding of the effect and the underlying mechanism. Using the model organisms Escherichia coli and Streptococcus pneumoniae, the researchers succeeded in identifying the molecular target (so-called target) of the active substance. Accordingly, Carolacton binds highly specifically to the key enzyme FolD of the C1 metabolism and thereby switches it off.

Binding properties and crystal structure analyzed

According to the researchers, the key enzyme FolD is involved in the formation of folic acid in the C1 metabolism (C stands for carbon). In further studies, the crystal structure and the binding properties of Carolacton to FolD could be shown in detail, reports the HZI. The C1 metabolism is one of the most important material cycles and "is highly conserved by all domains of life", emphasizes Prof. Irene Wagner-Döbler from the HZI. He provided important building blocks for growth, such as nucleic acids, amino acids and provitamins.

Cannot be used as an antibiotic?

Due to the key function of C1 metabolism, conserved genes for the key enzyme FolD can be found in many different species, including the mitochondria of human cells, reports Prof. Wagner-Döbler. "Due to the high degree of conservation between the bacterial FolD enzyme and the human enzyme in mitochondria, especially in the area of ​​the Carolacton binding sites, the natural product also inhibits the mitochondrial enzyme," continues the HZI researcher. For this reason, the use of Carolacton as an antibiotic in humans is hardly imaginable.

New approach to cancer therapy

However, the scientists found that the key enzyme FolD is overproduced in many tumor cells. "Carolacton would therefore be a very good starting point for use as an inhibitor in cancer therapy," reports the HZI. "In the first experiments, we were able to show inhibitory effects on various cancer cell lines tested," adds Prof. Müller. In the future, however, the pharmaceutical properties of the molecule would have to be further optimized. (fp)

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