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Insights into the central role of N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmU) in peptidoglycan metabolism and its potential as a therapeutic target.

Vijay SoniEric H RosennRamya Venkataraman
Published in: The Biochemical journal (2023)
Several decades after the discovery of the first antibiotic (penicillin) microbes have evolved novel mechanisms of resistance; endangering not only our abilities to combat future bacterial pandemics but many other clinical challenges such as acquired infections during surgeries. Antimicrobial resistance (AMR) is attributed to the mismanagement and overuse of these medications and is complicated by a slower rate of the discovery of novel drugs and targets. Bacterial peptidoglycan (PG), a three-dimensional mesh of glycan units, is the foundation of the cell wall that protects bacteria against environmental insults. A significant percentage of drugs target PG, however, these have been rendered ineffective due to growing drug resistance. Identifying novel druggable targets is, therefore, imperative. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is one of the key building blocks in PG production, biosynthesized by the bifunctional enzyme N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmU). UDP-GlcNAc metabolism has been studied in many organisms, but it holds some distinctive features in bacteria, especially regarding the bacterial GlmU enzyme. In this review, we provide an overview of different steps in PG biogenesis, discuss the biochemistry of GlmU, and summarize the characteristic structural elements of bacterial GlmU vital to its catalytic function. Finally, we will discuss various studies on the development of GlmU inhibitors and their significance in aiding future drug discoveries.
Keyphrases
  • cell wall
  • antimicrobial resistance
  • small molecule
  • current status
  • drug induced
  • multidrug resistant
  • human health
  • climate change
  • crystal structure
  • case control