The study revealing the undiscovering hot spots on the surface of bacteria’s critical enzyme; which could guide novel approaches to antibiotic design. As a novel antibacterial agents are needing to address the emergence of the global antibiotic resistance. Researchers have identified key sections of a bacterial enzyme that could be targeting with the new drugs to inhibit the spread of some bacterial infections.
Drug resistant bacterial infections have claimed the lives of millions of people worldwide. Because of the emergence of global antibiotic resistance, scientists are constantly searching for new antibacterial compounds. One attractive yet unexplored target for new antibiotics is an enzyme called MraY that aids the formation of the bacterial cell wall an essential component for all bacteria.
But the five types of natural products have being discovering to have inhibitory activities against MraY. However, exactly what goes on between the inhibitors and MraY on the molecular level has been unclear; hindering drug development. To get a closer look at these interactions, the researchers analysed the crystal structures of three types of nucleoside inhibitors that target the MraY liposidomycin / caprazamycin, capuramycin, and mureidomycin.
Enzyme targeting drugs inhibition
MraY is a promising candidate for antibiotic development because it is the target of five classes of naturally occurring nucleoside inhibitors with potent antibacterial activity. Although these natural products share a common uridine moiety, their core structures vary substantially and they exhibit different activity profiles.
Each type of MraY inhibitor has a distinct chemical structure and inhibition mechanism. The scientists used X-ray crystallography, a technique used to determine the atomic and molecular structure of a crystal, to analyse how the inhibitors bind to and interact with MraY. The structures revealed previously unknown spots on MraY’s surface where inhibitors bind to the enzyme as part of the interference process.
Types of nucleoside inhibitor
Specifically, the researchers finding all three types of nucleoside inhibitor; bind to one region on MraY’s surface, called the uridine binding pocket, in a similar manner. However, they each form different interactions with at least two other MraY binding sites. These binding sites and pocket could be possible targeting for new antibiotics designing to behaving like the inhibitors.
But an incomplete understanding of the structural and mechanistic basis of MraY inhibition; has hindering the translation of these compounds to the clinic. By using this knowledge of how the compounds bind to and interact with MraY; it would be possible to design an MraY inhibitor that targeting a novel combination of binding sites; with improving pharmacological properties and therapeutic potential.