Antibiotic development: a new target
Scientists have found out the properties of the target for new antibiotics
Oleg Lischuk, N+1
American and Japanese scientists have identified changes in the structure of an enzyme that serves as a promising target for new antibiotics when it interacts with a natural antibacterial compound. The results of their work are published in the journal Nature (Chung et al., Structural insights into inhibition of lipid I production in bacterial cell wall synthesis).
Employees of Duke University in Durham and Hokkaido University in Sapporo chose to study MraY (phospho-N-acetyl-muramoyl-pentapeptide-translocase), one of the key enzymes for the synthesis of bacterial wall peptidoglycans. Many natural antibacterial nucleoside inhibitors act on it, but antibiotics based on them have not yet been developed. In their work, the scientists used the MraY of the thermophilic rod-shaped bacterium Aquifex aeolicus and the natural inhibitor of this enzyme muraimycin D2 (MD2).
MraY (yellow and green) in the bacterial membrane and MD2 (pink).
Figure from the press release Study Provides A Structural Basis For The Development Of New Antibiotics - VM.
By X–ray crystallography, the researchers found that when binding to MD2, the enzyme significantly changes its conformation in the region of the active center with the formation of two "pockets" - nucleoside-binding and peptide-binding. Muraimycin binds to the nucleoside-binding pocket, after which another part of the molecule additionally enters the peptide-binding pocket, which increases its affinity (affinity) to MraY.
At the same time, MD2 does not bind to the three acid groups and the magnesium ion in the active center of the enzyme. This means that it does not directly block (according to the "key-lock" principle) the binding site of the MraY–UDP-N-acetylmuramoyl pentapeptide substrate, but partially overlaps with it, inactivating the enzyme.
The researchers note that such binding is possible due to the high conformational plasticity (the ability to change the spatial configuration) of MraY. Because of this, the enzyme serves as a target for numerous structurally diverse natural inhibitors.
"Many natural compounds bind to this enzyme in different ways. If we understand all the possible mechanisms of its inhibition, we will be able to develop drugs that act on it as specifically as possible," said senior author Seok-Yong Lee. According to scientists, the data they obtained will help in the development of inhibitors not only of MraY, but also of its paralogs WecA and TarO.
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20.04.2016