Antibiotic jewel loop

Antibiotic jewel loop

06/06/2019

Chemical synthesis shows: an antibiotic of the human nose works by translocation of protons

Antibiotic resistant bacteria are a growing health problem. New antibiotics face difficulties. German researchers have recently found:


The antibiotic of the human nose works by proton translocation

(c) Wiley-VCH

In the human nose, they discovered Lugdunin, a new cyclic peptide derived from the bacterium Staphylococcus lugdunensis that has potent antimicrobial activity, including resistant strains of Staphylococcus aureus.

Using synthetic variants, they have now succeeded in elucidating the mechanism of action. As they explain in the journal Angewandte Chemie, it is a transport of protons across the bacterial membrane.

The most interesting component of Lugdunin is its thiazolidine group (a pentagon of three carbon atoms, a nitrogen and a sulfur), which is part of the peptide core. This five ring cycle is reminiscent of a clasp that "adorns" the peptide ring.

Therefore, the researchers called the new class "fibupeptides" of fibula lat: clasp. The researchers had already succeeded in synthesizing the natural Lugdunin. At present, the team from the University of Tübingen and the University of Göttingen has optimized the synthetic route by realizing numerous natural product derivatives for a comprehensive study of the mechanism of action. until then unknown.

For example, they successively replaced each amino acid of the peptide core with the amino acid alanine, leaving the "ornamental clasp" and producing a fibupepdide in mirror. With the derivatives, they carried out activity tests.

In this way, the team of chemists, biochemists and microbiologists discovered that the cyclic structure of the peptide, the "clasp" thiazolidine, but also two of the amino acids, tryptophan and leucine, are essential to the l? antibiotic effect.

In addition, the peptide nucleus must always be composed of alternating amino acids D and L. Whether the original or the mirror image does not matter. "This goes against a stereospecific receptor-ligand interaction," said Nadine Schilling of Stephanie Grond's research group, "but for an interaction with a small molecule or ion."

In addition, the authors discovered that active derivatives of lugdunine break down the electrical potential (voltage difference between the outside and the inside) of bacterial cell membranes and thus kill bacteria. The incorporation of an additional tryptophan intensified the interactions with the membranes and enhanced the antibacterial effect.

Grond: "These results suggest a transport of ions across the bacterial membrane." To elucidate this, artificial vesicles with a pH gradient were generated on the surrounding solution. The addition of active fibopeptides resulted in a rapid pH balance – without destroying membranes or forming pores.

"The mechanism of action seems to be a translocation of protons across the membrane," Grond said. "Whether Lugdunin acts as a mobile carrier or as a proton channel remains to be clarified."

Angewandte Chemie: Press Release 15/2019

Author: Stephanie Grond, Eberhard-Karls University of Tübingen (Germany), https: //www.mnf.uni-tuebingen.de/fachbereiche/chemie/institute/organische-chemie …

Angewandte Chemie, PO Box 101161, 69451 Weinheim, Germany.

Original publication:

https://doi.org/10.1002/ange.201901589

Further information:

http://presse.angewandte.de

Dr. Karin J. Schmitz | Society of German Chemists e.V.