Exploiting selected Mur enzyme characteristics for antibacterial drug design

Bacterial species demonstrate remarkable adaptability in hostile environments and develop resistance to multiple antibacterial molecules, creating significant challenges for infection treatment in clinical settings. At the core of this challenge lies peptidoglycan, a key component in cell wall synthesis that provides both structural integrity and environmental protection for bacterial cells. The peptidoglycan biosynthesis pathway operates across three distinct cellular compartments: the cytoplasm, membrane, and periplasmic space. The process initiates in the cytoplasm with nucleotide precursor formation, where Mur family enzymes transform UDPGlcNAc into UDP-MurNAc-pentapeptide (UDP-Mpp). Simultaneously, undecaprenyl phosphate is produced on the cytoplasmic side (inner membrane), with membrane proteins MraY and MurG serving as essential catalysts for lipid I and lipid II formation. This review provides updated insights into Mur family proteins by focusing on their physicochemical properties, evolutionary relationships, post-translational modifications (PTMs), structural characteristics (functional domains and binding site properties including number and type of binding site residues) and dynamic behaviour. Given the limited commercial availability of peptidoglycan precursors, special emphasis is placed on understanding these enzymes role in peptidoglycan biosynthesis. Furthermore, the review emphasizes existing inhibitors and current research efforts to develop novel targeted compounds based on structure-activity relationships of known inhibitors. The information presented in this review paves the way for developing promising antibacterial therapeutics designed to tackle the challenges posed by multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogenic bacterial strains.