Directly in the nose: antimicrobial peptide fights pathogenic bacteria

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As humans, we are constantly accompanied by billions of microorganisms that live
As humans, we are constantly accompanied by billions of microorganisms that live on our skin or in our airways in the form of our microbiome. One of these products is lugdunin, a cyclic peptide that was discovered in a bacterium in the human nose in 2016. Researchers from the Universities of Göttingen, Erlangen-Nuremberg and Tübingen have now decoded the function of the molecule for the first time. Photo: University of Erlangen-Nuremberg

Research team involving the University of Göttingen decodes molecular function

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As humans, we are constantly accompanied by billions of microorganisms that live on our skin or in our airways in the form of our microbiome. The relationships between these microorganisms are a rich source of previously unknown metabolic products that are beneficial to humans. One of these products is lugdunin, a cyclic peptide that was discovered in a bacterium in the human nose in 2016 and has shown a promising effect against antibiotic-resistant Staphylococcus pathogens in studies conducted by the University of Tübingen. Researchers from the Universities of Göttingen, Erlangen-Nuremberg and Tübingen have now decoded the function of the molecule for the first time: Through interactions between lugdunin molecules, it forms nanometer-sized channels in cell membranes that can transport ions, leading to the death of a bacterial cell. The new findings lay the foundation for understanding the mode of action of lugdunin in the human microbiome and have been published in the journal Nature Communications.

Researching the exact mode of action of small molecules in cell membranes is very difficult, as the membranes of living organisms are highly complex systems consisting of millions of interconnected components. The scientists therefore used simplified models of these membranes. -Such model membranes consist of only the simplest components, the lipids, and thus enable a targeted investigation of the interaction of lugdunin with cell membranes without other interfering biomolecules," explains first author Dr. Dominik Ruppelt from the University of Göttingen. In order to obtain lugdunin in sufficiently large quantities, the researchers produced it by chemical synthesis and introduced some changes to the structure of the molecule. Using this approach, they were able to discover that individual lugdunin molecules join together in a membrane and stack on top of each other. This creates a water-filled, tubular structure with a diameter of less than one nanometer. This spans the membrane and enables the transport of ions. -Using a special technique, we were able to measure the tiny flow of ions across the membrane and thus prove that Lugdunin fights bacterial cells in this way," says Ruppelt.

In addition to experimental methods, the researchers also used computer simulations to substantiate their findings. By simulating the behavior and interaction of molecules using calculations, they obtained computer-generated images and videos that show exactly how such a stable lugdunin nanotube forms and how it transports ions across membranes.

Understanding the mode of action of lugdunin is of great interest in the discussion about interactions within the microbiome in healthy people. -The mechanism of nanotube formation that we have proposed has not yet been described for any other naturally occurring cyclic peptide," says Claudia Steinem from the Institute of Organic and Biomolecular Chemistry at the University of Göttingen. -Our results therefore hold great potential for the development of further substances that regulate the microbiome, and in particular for further research into the role of lugdunin in the human body.

Original publication: Dominik Ruppelt et al. The antimicrobial fibupeptide lugdunin forms water-filled channel structures in lipid membranes .Nature Communications 2024. doi: 10.1038/s41467’024 -47803-6 .