(ORDO NEWS) — Scientists from the Institute of Bioorganic Chemistry. MM Shemyakina and Yu. A. Ovchinnikov of the Russian Academy of Sciences, MIPT and HSE studied the interaction of a known natural antibiotic with its target using molecular modeling. These data will help to develop effective new types of antibiotics.
The overuse of antibiotics leads to the rapid development of bacterial resistance, which poses a threat to human health around the world. Therefore, the search and development of new classes of antibacterial agents with a mode of action that is not used today is extremely relevant. In microbiology, small antimicrobial proteins called lantibiotics are known to have bactericidal potential.
Nisin, the best studied lantibiotic, was discovered even before Alexander Fleming’s discovery of penicillin. Nisin has never been used in clinical practice due to instability in the human body. However, it has been widely used as a food preservative since 1953 without any signs of developing resistance. Nisin effectively fights, first of all, against bacteria with a single-layer membrane. There is evidence of activity in combination with metal ions against several strains with a two-layer wall.
The lantibiotic kills bacteria by destroying the membrane and stopping cell wall synthesis. It actively interacts with a specific target in the cell membrane – lipid II. Despite the popularity and active use in the food industry, the mechanism of the antimicrobial action of nisin at the atomic level remains unexplored.
In their work, the authors first looked for complexing states of both isolated molecules in their natural environment. The full-sized nisin and its N-terminal recognition module were placed in an aqueous solution, and lipid II was inserted into a model bacterial membrane.
Additional modeling was performed for molecules in control media in which experiments had previously been performed. Next, the scientists carried out molecular modeling of the active part of nisin in the presence of an analogue of the “head” of lipid II in an aqueous solution. The results are published in the journal Scientific Reports.
“The data obtained helped to study the spontaneous formation of complexes and the mechanism of recognition by molecules of each other,” explains one of the authors, Anton Chugunov, associate professor at the Physics and Technology School of Physics and Research named after Landau MIPT and Senior Researcher, IBCh RAS.
After that, the authors developed a computational technique of “pyrophosphate pharmacophore energy”, which helps to easily identify in the trajectories of molecular dynamics the nisin conformation that can form a complex with lipid II.
Finally, based on the most frequent conformations of both molecules, the scientists constructed a putative complex of the nisin recognition module with lipid II in the model bacterial membrane, which remained stable over a long simulation period. It turned out that nisin forms a stable complex with two conformations (states) of lipid II.
“Our results show which lipid II conformations can interact with antibiotics. Previous studies did not take into account the lipid environment, which significantly influences target behavior. Our calculations showed that only 20-30% of the surface of the head group is available for interaction in the natural environment.
This severely restricts the freedom of choice of positions for binding to nisin. Apparently, up to just two conformations. Thus, it becomes clear how to position the antibiotic molecule so that it acts the same as nisin, or even more efficiently. The binding model we have developed will simplify the search for candidate molecules, which can then be experimentally investigated for their effectiveness against bacteria, ”adds Roman Efremov, professor at the Physics and Technology School of Physics and Research named after M.V. Landau MIPT,
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