At the top of the nineteenth century, the German pathologist Ludwig Thudichum isolated previously unknown fatty substances (lipids) from the brain. He named the brand new class of molecules sphingolipids — after the Greek mythical creature Sphinx, out of respect for “the various riddles it posed to the researcher.”
Since then, many diseases have been discovered which might be attributable to a faulty sphingolipid metabolism within the brain, including Fabry’s disease and Gaucher’s disease. Sphingolipids even have been connected to infectious diseases, for example viral infections with Ebola, measles or Covid-19 in addition to bacterial infections with Pseudomonas aeruginosa or Staphylococcus aureus, which may cause middle ear infection, skin and lung infections and plenty of other diseases. In these infections the degradation of the molecule sphingomyelin by the enzyme sphingomyelinase is usually a vital step. Nonetheless, visualizing the enzyme’s activity was previously unattainable.
A Latest Chemical Probe to Fill the Gap
Researchers from Würzburg and Berlin have now succeeded in developing a sphingomyelin derivative that might be used to visualise the distribution of sphingomyelin and the activity of sphingomyelinase in infection processes.
The scientists are a part of the Research Training Group 2581 “Metabolism, topology and compartmentalisation of membrane proximal lipid and signalling components in infection” funded by the German Research Foundation (DFG). Therein chemists, physicists and biologists collaborated to synthesize novel chemical compounds and test their applicability in infection research.
“The brand new molecules are trifunctional sphingomyelins based on the natural product sphingomyelin and equipped with three additional functions. It was difficult to design such molecules, which might be accepted by the metabolism like its natural origin” says Professor Jürgen Seibel from the Institute of Organic Chemistry at Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.
Sphingomyelin Degradation During Development of Chlamydia Bacteria Imaged
The scientists demonstrated the function of their newly developed molecules not only by determining the activity of a bacterial sphingomyelinase on the surface of human cells. In addition they visualised sphingomyelin degradation inside human cells through the course of an infection with intracellular Chlamydia bacteria, that are known to contaminate the human genital tract and are suspected to contribute to the event of cancer in infected tissues.
Inside their host cells Chlamydia form a replicative organelle called an inclusion. The researchers showed that chlamydial inclusions mainly contain the cleaved types of the trifunctional sphingomyelins. Using so-called expansion microscopy and click-chemistry, they observed that the proportion of metabolised sphingomyelin molecules increased through the maturation of non-infectious to infectious Chlamydia particles. By with the ability to visualise this infection process recent targeted strategies against these infections can now be developed.
“The brand new chemical tool will definitely serve us well and readily might be utilized in many laboratories,” Professor Seibel states. “Our aim is to make use of it to discover novel anti-infectious or immunotherapeutic strategies for drug development that might be used to combat infectious diseases by modulating sphingolipid metabolism.”
