A new target to fight the dangerous melioidosis infection has been identified

A new target to fight the dangerous melioidosis infection has been identified

by Ronja Münch, Leibniz Institute for Natural Product Research and Infectious Biology – Hans Knöll Institute (Leibniz-HKI)

The active center of the enzyme BurG, which forms a highly reactive chemical compound that plays a vital role in melioidosis. Credit: Michael Groll/Felix Trottmann

Researchers at the Leibniz Institute for Natural Product Research and Infectious Biology – Hans Knöll Institute (Leibniz-HKI) in Jena, Germany have identified an enzyme that is a promising new therapeutic target in the fight against the dangerous bacterial disease melioidosis. It helps the pathogenic bacterium Burkholderia pseudomallei to create a toxic molecule that is critical in the infection process. The results were published in Natural chemistry.

Melioidosis is a life-threatening disease caused by the bacterium Burkholderia pseudomallei. “Without treatment, the disease is usually fatal,” explains Christian Hertweck, Head of Biomolecular Chemistry at Leibniz-HKI and Professor of Natural Product Chemistry at the Friedrich Schiller University of Jena. “And even antibiotic treatment often drags on for many months and is not always successful, because common drugs against these pathogens do not work well.”

His research group therefore wanted to understand the infection mechanisms of this bacterium and came across a possible new starting point for fighting the disease. “We found an enzyme that synthesizes a molecular structure central to infection,” explains Felix Trottmann, first author of the study.

The discovered BurG enzyme forms a cyclopropanol ring, a highly reactive chemical functional group, from a precursor molecule. In previous studies, Trottmann was able to demonstrate that this structure is also produced by other pathogenic bacteria of the genus Burkholderia and apparently has an important role in infection. If the biosynthetic pathway for this molecule is turned off by mutations, the bacteria are far less dangerous.

The research team also elucidated the 3D structure of the enzyme in collaboration with TU Munich. “As a next step, we can now try to design active compounds that inhibit the enzyme and thereby make the bacteria less virulent,” explains Trottmann. According to current knowledge, the enzyme is found only in bacteria and not in humans. “So the hope is that we’ll be able to specifically inhibit the bacteria,” Hertweck says. The immune system could then deal with them more easily.

To understand the biosynthesis of the molecular structure central to infection, the researchers examined the gene cluster that contains the DNA instructions for its creation. They conducted laboratory experiments using Burkholderia thailandensis, which is very similar to Burkholderia pseudomallei, but much safer to work with.

Melioidosis occurs mainly in Southeast Asia and Australia. But experts warn that the disease can spread further. For example, the US Centers for Disease Control and Prevention (CDC) was able to trace the cause of four cases of melioidosis, two of which were fatal, to an aromatherapy spray last year. A closely related species, B. mallei, which also produces a cyclopropanol ring, was used as a biological weapon in World War I and World War II. And B. pseudomallei has also been investigated as such in some countries.


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More information:
Felix Trottmann et al, Pathogenic bacteria remodel a central metabolic enzyme to form a cyclopropanol head, Natural chemistry (2022). DOI: 10.1038/s41557-022-01005-z

Provided by the Leibniz Institute for Natural Product Research and Infectious Biology – Hans Knöll Institute (Leibniz-HKI)

Citation: New target identified to combat dangerous melioidosis infection (2022, August 1) Retrieved August 1, 2022, from https://medicalxpress.com/news/2022-08-combat-dangerous-melioidosis-infection.html

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