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A team of researchers from the universities of Tübingen and Göttingen, as well as the German Infection Research Center, has studied the mode of action of a new clbad of highly effective antibiotics against pathogens multiresistant. The so-called fibupeptides interfere with the energy supply of the bacterial cell, resulting in their death. The results of the research were published recently in the journal Angewandte Chemie.
In 2016, as part of a widely recognized study, a team of Tübingen researchers led by Professor Andreas Peschel discovered the first fibupeptide. It is produced by the microbiome itself and scientists call it lugdunin, thus calling it the bacterium Staphylococcus lugdunensis that produces the substance and resides in the lining of the nose. Lugdunin has an unusual chemical structure and is therefore a potential prototype for a completely new clbad of antibiotics. Among other things, it is effective against one type of methicillin-resistant bacteria called Staphylococcus aureus (MRSA), which is particularly dangerous to humans. They are particularly feared in hospitals where they often target immunocompromised patients. According to a study published in The Lancet Infectious Diseases in November 2018, approximately 670,000 multidrug-resistant pathogen infections resulting in the death of 33,000 patients were registered in the European Union alone in 2015.
The researchers have now synthesized the chemical variations of lugdunine and determined the structural chemical elements responsible for its effects, which also give insights into the mode of action of the antibiotic. "Every bacterial cell requires a so-called membrane potential for living," says Schilling. "This means that a pathogen needs different concentrations of electronically charged particles in the cell relative to its external environment.Fluupeptides like lugdunine are able to transport positively charged hydrogen ions across the membrane and thus to dissipate this membrane potential, resulting in a kind of energy shutdown, "says the researcher. As a result, the bacterial cell dies.
Mirror image structure test
The increase in antibiotic resistance is an increasingly difficult challenge for the treatment of bacterial infections. Many of the new antibiotics currently in use differ only slightly from antibiotics for which known multidrug resistance already exists. It may be just a short period of time for these new drugs to become ineffective.
Therefore, new antibiotic structures such as lugdunine and their modes of action are of great interest. "
Stephanie Grond, Professor of Organic Chemistry and Natural Compounds Research at the University of Tübingen
"Lugdunine has a unique structure," she explains, "consisting of a core of amino acid components (a peptide structure) with a characteristic sulfur-to-nitrogen bond, called thiazolidine, that looks like an ornamental clasp. (called "fibula" C is the reason why this new clbad of agents has been called fibu-peptides: the thiazolidine nucleus is one of the essential structures for antibacterial effect.
In order to identify the structures responsible for the antibiotic effect of lugdunine, the team of researchers synthesized many derivatives of lugdunine, gradually modifying certain parts of the chemical structure and determining the l? Antibiotic activity at each stage. "As a rule, many of the known peptide antibiotics have very specific effects," says Schilling, "for example, their structure allows them to bind to enzymes and block the pathways necessary for the development of new bacterial cells." However, lugdunine is different, as has shown a test with its mirror image structure.
"A substance and its inverted image structure may be considered as a right hand and a left hand.They are not identical, just as a left hand does not fit in a right-handed glove and the substances therefore have effects different in the space, "the researcher explains. "However, the antibiotic effect remained unchanged in a mirror structure of chemically synthesized lugdunine, so we could rule out that the antibiotic effect is based on spatial interactions." A lack of spatial interactions is advantageous to avoid resistance and it has not been possible to create resistance to lugdunine under laboratory conditions.
In-depth preclinical and clinical trials are needed to determine whether fibupeptides can be used in the future as candidates for treatment. The researchers involved aim to determine whether lugdunine and related substances are effective and safe for the treatment of multidrug-resistant pathogens. Investigations are underway in the Tübingen Excellence Center "Microbial Control to Fight Infections", launched in early 2019, and in other networks.
Source:
German Infection Research Center
Journal reference:
Grond, S. et al. (2019) Synthetic badogues of lugdunine reveal essential structural motifs for antimicrobial action and proton translocation ability. Angewandte Chemie. doi.org/10.1002/anie.201901589.
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