TÜBINGEN. A team of researchers from the universities of Tübingen and Göttingen and the German Infection Research Center has studied the mode of action of a new class of highly effective antibiotics against multidrug-resistant pathogens. As Nadine Schilling of the Institute of Organic Chemistry at the University of Tübingen explains, so-called fibupeptides affect the energy supply of the bacterial cell, resulting in its death. Scientists in Tübingen discovered in 2016, as part of a widely acclaimed study, a first fibropeptide manufactured by our microbiome itself. Scientists have called the substance Lugdunin, according to its producer, the bacterium Staphylococcus lugdunensis, which lives in the human nasal mucosa. Lugdunin has an unusual chemical structure and can be a prototype for a whole new class of antibiotics.
It acts especially against particularly dangerous bacteria of the species Staphylococcus aureus (MRSA) resistant to methicillin. MRSA is particularly feared in clinics because it often infects immunocompromised patients. According to one study, in the European Union alone, there were approximately 670 000 multidrug-resistant pathogen infections in 2015, which caused the death of 33 000 patients. The researchers have now produced various substances of Lugdunin by chemical synthesis and determined the necessary for the action of the chemical structural elements of Lugdunine. This gave indications on the mechanism of action of the antibiotic. "Every bacterial cell needs a so-called transmembrane voltage to live," says Schilling. "In other words, it is crucial for the pathogen that the concentrations of electrically charged particles inside and outside the cell differ." Fibupeptides such as lugdunine are able to transport positively charged hydrogen ions across the membrane and suppress the charge differential. "This causes some kind of power failure," says the researcher. The bacterial cell dies.
Great interest in structures
The development of antibiotic resistance makes the treatment of bacterial infections increasingly difficult. Many of the new antibiotics currently in use differ only slightly from those already known for their multiple resistance. It may not be a matter of time before these new drugs become ineffective. "Therefore, the interest in new antibiotic structures such as Lugdunin and their mode of action is enormous," says Stephanie Grond, professor of organic chemistry and natural product research at the University of California. University of Tübingen. Lugdunin has a unique chemical structure, explains Grond. It consists of a cycle of amino acid building blocks (a peptide structure) incorporating a sulfur-nitrogen ring compound called thiazolidine, such as a jewel loop (Latin fibula). The special Thiazolidinring is one of the constituent elements of Lugdunin, essential for the antibacterial effect.
In order to identify the structures necessary for the antibiotic effect of Lugdunins, researchers have developed various derivatives. Gradually, parts of the chemical structure were changed and each determined the activity of the antibiotic. In order to clarify whether fibupeptides are suitable in the future as drug candidates for therapeutic application, further studies are needed in the future. Researchers also wish to discover, in the context of Tübingen's pole of excellence "Fight against microorganisms for the control of infections", that lugdunine and its related substances can be used effectively and safely in the future for the treatment of multidrug-resistant infections. (Em)