MraY: An emerging therapeutic target in bacterial peptidoglycan biosynthesis for the discovery of novel antibiotics from natural and synthetic origin

The escalating global threat of antibiotic resistance highlights the urgent need for innovative therapeutic strategies targeting essential bacterial pathways. The bacterial enzyme MraY transferase, a key component of peptidoglycan biosynthesis, is critical for bacterial survival but remains untargeted by any marketed drug. This makes it an appealing antibacterial target without risk of cross-resistance to current antimicrobial drugs. Additionally, Recent advancements, including discoveries of novel nucleoside-based inhibitors such as caprazamycins, muraymycins, and riburamycins, have demonstrated promising broad-spectrum antibacterial activity, efficacy against resistant strains, and low toxicity. These inhibitors and newer non-nucleoside and non-traditional compounds showcase significant potential to address the growing resistance crisis. However, an incomplete understanding of the structural and mechanistic basis of MraY inhibition continues to hinder the clinical translation of these promising molecules. This review seeks to fill the existing knowledge gap by providing an updated analysis of nucleoside and non-nucleoside MraY inhibitors, their binding interactions, and pharmacological behaviors. Additionally, it highlights opportunities for medicinal chemists to optimize structure-activity relationships and explore species-specific or broad-spectrum therapeutic designs. By integrating recent research and insights, this review aims to catalyze the development of novel, clinically viable antibacterials targeting MraY, contributing to the global fight against antibiotic resistance. • MraY is a pertinent target for developing novel antibiotics. • The enzyme is essential for bacterial peptidoglycan biosynthesis. • Structural insights of MraY and its similarity with human GPT have been explored. • An updated overview of nucleoside and non-nucleoside MraY inhibitors is provided. • An in-depth SAR of MraY inhibitors can guide the design of new MraY inhibitors.