A new target identified to combat a dangerous Melioidosis infection

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Melioidosis is a life-threatening disease caused by the bacterium Burkholderia pseudomallei. German researchers have now identified a promising new therapeutic target to combat the dangerous disease - an enzyme within the bacterium that is critical for the infection process. The results from the research are published in Nature Chemistry.

Melioidosis mainly occurs in tropical areas of the world - in northern Australia and throughout Southeast Asia. In Queensland, infection occurs mainly in north Queensland but can occur in southern parts of the state. And experts warn that the disease could spread further, including by unconventional ways. In 2021 the US Centers for Disease Control and Prevention (CDC) were able to trace the cause of four cases of melioidosis - two of which were fatal - to an aromatherapy spray.

The research group at Germany’s Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI) wanted to understand the bacterium's infection mechanisms and has come across a possible new starting point for combating the disease. 

Christian Hertweck, head of the Biomolecular Chemistry Department at Leibniz-HKI and professor of natural product chemistry at Friedrich Schiller University said: "Without treatment, the disease is usually fatal. And even antibiotic treatment often drags on for many months and is not always successful because common drugs do not work well against these pathogens."

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

Felix Trottmann, first author of the study said that the newly discovered enzyme helps the pathogenic bacterium B. pseudomallei construct a toxic molecule necessary for infection to occur. "We have found an enzyme that synthesizes a molecular structure central to the infection.” 

The research team has also described the 3D structure of the enzyme. 

The enzyme BurG 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 in the genus Burkholderia and apparently has an important role in infection. If the biosynthetic pathway for this molecule is switched off by mutations, the bacteria are far less dangerous.

"In a next step, we can now try to design active compounds that inhibit the enzyme and thus make the bacteria less virulent," Trottmann said. 

According to current knowledge, the enzyme is only found in bacteria and not in humans. "The hope is therefore to be able to specifically inhibit the bacteria," Hertweck said. The immune system could then deal with them more easily.