Advances in UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Covalent Inhibition

Abstract

Peptidoglycan is a cross-linked polymer responsible for maintaining the bacterial cell wall integrity and morphology in Gram-negative and Gram-positive bacteria. The peptidoglycan pathway consists of the enzymatic reactions held in three steps: cytoplasmic, membrane-associated, and periplasmic. The Mur enzymes (MurA-MurF) are involved in a cytoplasmic stage. The UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme is responsible for transferring the enolpyruvate group from phosphoenolpyruvate (PEP) to UDP-N-acetylglucosamine (UNAG) to form UDP-N-acetylglucosamine enolpyruvate (EP-UNAG). Fosfomycin is a natural product analogous to PEP that acts on the MurA target enzyme via binding covalently to the key cysteine residue in the active site. Similar to fosfomycin, other MurA covalent inhibitors have been described with a warhead in their structure that forms a covalent bond with the molecular target. In MurA, the nucleophilic thiolate of Cys115 is pointed as the main group involved in the warhead binding. Thus, in this minireview, we briefly describe the main recent advances in the design of MurA covalent inhibitors.

Synthesis and inhibitory activity against MurA and MurZ enzymes of 4H-pyrano[2,3-d]pyrimidine–1H-1,2,3-triazole hybrid compounds having piperidine and morpholine rings

“…The target for docking simulations was the crystallographic structure of substrate UDP-N-acetylglucosamine of enzyme 1UAE. 5 The free energies and binding modes of these most active compounds (against MurA enzyme) were studied through Schro ¨dinger software 39 on enzyme 1UAE. The active interactions of ligands 12d, 12e, and 13b as well as co-crystal UD1 are presented in Table 4 and Fig.…”

“…3 PGN is one of the classic drug targets, but remains a notable target in the design of compounds with antimicrobial activity. 4,5 The inhibition against cell wall biosynthesis is a major target of antibiotics, including beta-lactam and glycopeptide antibiotics.…”

“…[7][8][9]11 These are attractive selective targets to develop agents against Gram-positive and Gram-negative pathogenic bacteria. 5,6,10,13 These enzymes, including Murs (MurA, MurB, MurC, MurD, MurE, MurF, and MurZ), [14][15][16] catalyse the last six steps in the formation of the final cytoplasmic peptidoglycan biosynthesis precursor uridine 5 0 -diphosphate-N-acetylmuramyl-pentapeptide (UDP-MurNAc-pentapeptide). 7,15 UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is an important enzyme involved in the first cytosolic step of bacterial cell wall synthesis.…”

“…3 PGN is one of the classic drug targets, but remains a notable target in the design of compounds with antimicrobial activity. 4,5 The inhibition against cell wall biosynthesis is a major target of antibiotics, including beta-lactam and glycopeptide antibiotics. The attractive selective targets to develop agents against Gram-positive and Gram-negative pathogenic bacteria are the enzymes participating in the biosynthesis of the bacterial cell wall, especially its essential component, i.e.…”

Role of UDP‐N‐acetylmuramic acid in the regulation of MurA activity revealed by molecular dynamics simulations

“…Currently, the PEP analogue fosfomycin is the only agent approved by the United States Food and Drug Administration for clinical use in the inhibition of MurA, primarily for the treatment of cystitis. Thus, it is important to highlight the increasing challenges posed by fosfomycin‐resistant microorganisms and the emergence of mutations that challenge fosfomycin effectiveness, demanding the use of covalent inhibitors of the MurA enzyme (Lima et al, 2021; Falagas et al, 2019; Xin et al, 2022; De Oliveira et al, 2022).…”