Energy supply of multidrug-resistant germs

The fight against multidrug-resistant germs is becoming increasingly difficult year after year as the range of antibiotics still effective decreases. The new active ingredients are therefore in great demand. Researchers at the University of Tübingen have studied a promising new class of antibiotics and discovered the mechanism by which these active substances destroy bacteria.

Tübingen – A team of researchers from the universities of Tübingen and Göttingen and the German Infection Research Center has studied the effects of a new class of highly effective antibiotics against multidrug-resistant pathogens. As Dr. Nadine Schilling, of the Institute of Organic Chemistry at the University of Tübingen, discovered that the so-called fibupeptides alter the energy supply of the bacterial cell, resulting in its death.

By 2016, scientists in Tübingen had discovered a first fibropeptide produced 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 a study published in November 2018, in the EU alone in 2015, approximately 670 000 multidrug-resistant pathogen infections were diagnosed, resulting in the death of 33 000 patients.

How does the new antibiotic work?

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. Thus, they received indications about 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 essential 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 to cancel the charge differential. "This causes some kind of power failure," says the researcher. The result: the bacterial cell dies.

Miniaturized high throughput method

3:05:19 – Newer antibiotics are more in demand in the era of increasing resistance. Swiss researchers have developed a promising method that allows them to quickly test a very large number of molecules to determine their antibiotic effect. For this, they modernized and miniaturized the penicillin discoverer method, Alexander Fleming. read

Special structure of Lugdunin

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 is therefore quite possible that even these new drugs are ineffective in a short period of time. "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 structural model: the thiazolidine ring, the "jewelry loop", is lined with a yellow paper.
(Photo: University of Tübingen, José M. Beltrán-Beleña)

Lugdunin has a unique chemical structure, says Grond. It consists of a ring of amino acid building blocks (a peptide structure) incorporating a characteristic sulfur-nitrogen ring compound called thiazolidine, such as a jewelry loop. Loop means fibula in Latin, which is why the new class of substances has been called Fibupeptide. The special Thiazolidinring is one of the constituent elements of Lugdunin, essential for the antibacterial effect.

Mirror image with the same effect

In order to identify the structures of lugdunine necessary for the antibiotic effect, the research team produced a large number of offspring. Gradually, parts of the chemical structure were changed and each determined the activity of the antibiotic. "Many previously known peptide antibiotics are usually very specific," says Schilling. For example, they could bind to an enzyme by their spatial structure, block the necessary processes and thus prevent the formation of new bacterial cells. This is different with the Lugdunin, as revealed by a test with its structural mirror image.

"A fabric and its structural reflection can be imagined as a non-congruent right hand and left hand.The left hand does not fit in a straight glove, so the substances related to the mirrors are not spatially similar," says the researcher . "The mirror Lugdunin, which was produced by chemical synthesis, but its antibiotic effect has been preserved, so we could exclude that it is based on a spatial interaction." For the development of resistance, the absence of a such spatial interaction is an advantage, and resistance to Lugdunin could not be generated in laboratory experiments.

The laboratory file "Antibiotic resistance"
Would you like to know more about "multi-resistant germs"? Then visit our "Antibiotic Resistance" folder where we have compiled articles on important advances in medical research.

Clinical studies in planning

In order to clarify if fibupeptides are suitable in the future as drug candidates for therapeutic application, further preclinical and clinical studies will be needed in the future. The researchers involved have been involved in the running since early 2019. The Tübingen Excellence Group, "Control of micro-organisms to fight infections", discovered that lugdunine and its related substances could be used. effectively and safely in the future for the treatment of multi-resistant bacteria infections.

Original publication: Nadine A. Schilling, Anne Berscheid, Johannes Schumacher, Julian S. Saur, Martin C. Konnerth, Sebastian N. Wirtz, Jose Beltran-Belena, Alexander Zipperer, Bernhard Krismer, Andreas Peschel, Hubert Kalbacher, Heike Brötz-Oesterhelt, Claudia Steinem, Stephanie Grond: Lugdunin's synthetic analogs reveal essential structural motifs for antimicrobial action and proton translocation ability, Angewandte Chemie (2019); DOI: 10.1002 / anie.201901589

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Dr. K. G. Rijkhoek, A. Karbe, University Eberhard Karls Tübingen, 72074 Tübingen