Phosphinate Inhibitors of UDP‐<i>N</i>‐Acetylmuramoyl‐<scp>L</scp>‐Alanyl‐<scp>D</scp>‐Glutamate: <scp>L</scp>‐Lysine Ligase (MurE)

Štrancar, Katja; Boniface, Audrey; Blanot, Didier; Gobec, Stanislav

doi:10.1002/ardp.200600191

Cited by 34 publications

(18 citation statements)

References 14 publications

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“…Promisingly, Strancar et al . reported that some phosphinate inhibitors of MurD also inhibit MurE with IC 50 values in the micromolar range (Strancar et al ., ). Sulphonamide derivatives based on naphthalene‐ N ‐sulphonyl‐ d ‐glutamic have then been designed as transition‐state analogue inhibitors of MurD (Kotnik et al ., ; Humljan et al ., ; Sosic et al ., ; Simcic et al ., ).…”

Section: Development Of Multi‐target Mur Ligase Inhibitorsmentioning

confidence: 97%

The biology of Mur ligases as an antibacterial target

Kouidmi

Levesque

Paradis-Bleau

2014

Molecular Microbiology

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SummaryWith antibiotic resistance mechanisms increasing in diversity and spreading among bacterial pathogens, the development of new classes of antibacterial agents against judiciously chosen targets is a highpriority task. The biochemical pathway for peptidoglycan biosynthesis is one of the best sources of antibacterial targets. Within this pathway are the Mur ligases, described in this review as highly suitable targets for the development of new classes of antibacterial agents. The amide ligases MurC, MurD, MurE and MurF function with the same catalytic mechanism and share conserved amino acid regions and structural features that can conceivably be exploited for the design of inhibitors that simultaneously target more than one enzyme. This would provide multi-target antibacterial weapons with minimized likelihood of targetmediated resistance development.

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Section: Development Of Multi‐target Mur Ligase Inhibitorsmentioning

confidence: 97%

The biology of Mur ligases as an antibacterial target

Kouidmi

Levesque

Paradis-Bleau

2014

Molecular Microbiology

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“…Its high (stereo)specificity for D-glutamic acid has been shown by studying structurally related analogues tested as substrates or inhibitors. 21,22 There have been several successful attempts to identify MurD inhibitors by using the transition-state hypothesis [23][24][25][26][27][28][29] and it was suggested that D-glutamic acid represents an essential fragment of a potent inhibitor. 25,26 Based on this rationale we recently synthesized a series of sulfonamide derivatives of D-glutamic acid, as analogues of the tetrahedral intermediate (unpublished results).…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Characterization of Enantiomeric Glutamic Acid Derivatives as Potential Transition State Analogue Inhibitors of MurD Ligase

Kotnik¹,

Humljan²,

Contreras‐Martel

et al. 2007

Journal of Molecular Biology

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“…The UDP-MurNAc:L-alanine ligase (MurC), encoded by the murC gene, represents such an interesting candidate for drug development (9,10). Recently, different phosphinic acid derivatives and substrate analogues have been identified as Mur ligase inhibitors (11,12).…”

mentioning

confidence: 99%

The MurC Ligase Essential for Peptidoglycan Biosynthesis Is Regulated by the Serine/Threonine Protein Kinase PknA in Corynebacterium glutamicum

Fiuza

Canova

Patin

et al. 2008

Journal of Biological Chemistry

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The Mur ligases play an essential role in the biosynthesis of bacterial cell-wall peptidoglycan and thus represent attractive targets for the design of novel antibacterials. These enzymes catalyze the stepwise formation of the peptide moiety of the peptidoglycan disaccharide peptide monomer unit. MurC is responsible of the addition of the first residue (L-alanine) onto the nucleotide precursor UDP-MurNAc. Phosphorylation of proteins by Ser/Thr protein kinases has recently emerged as a major physiological mechanism of regulation in prokaryotes. Herein, the hypothesis of a phosphorylation-dependent mechanism of regulation of the MurC activity was investigated in Corynebacterium glutamicum. We showed that MurC was phosphorylated in vitro by the PknA protein kinase. An analysis of the phosphoamino acid content indicated that phosphorylation exclusively occurred on threonine residues. Six phosphoacceptor residues were identified by mass spectrometry analysis, and we confirmed that mutagenesis to alanine residues totally abolished PknA-dependent phosphorylation of MurC. In vitro and in vivo ligase activity assays showed that the catalytic activity of MurC was impaired following mutation of these threonine residues. Further in vitro assays revealed that the activity of the MurC-phosphorylated isoform was severely decreased compared with the non-phosphorylated protein. To our knowledge, this is the first demonstration of a MurC ligase phosphorylation in vitro. The finding that phosphorylation is correlated with a decrease in MurC enzymatic activity could have significant consequences in the regulation of peptidoglycan biosynthesis.Due to the increasing number of antibiotic-resistant strains and the emergence of new pathogenic microorganisms, one of the biggest challenges for modern biomedical research is the continuous development of new antimicrobial drugs targeting bacterial essential mechanisms such as cell division or peptidoglycan (PG) 4 biosynthesis (1). The bacterial cell wall PG is a giant molecule that sustains the shape of the bacterial cell and contains the outward forces generated in maintaining an osmotic pressure gradient against the environment. Without this PG layer the cell integrity would be ruptured, and this could lead to cell death. Therefore the PG biosynthesis machinery represents a promising source of putative targets for antibacterial chemotherapy (2, 3).The biosynthesis of bacterial PG is a complex two-stage process (4). The first stage involves the assembly of the disaccharide peptide monomer unit by enzymes located in the cytoplasm or at the inner surface of the cytoplasmic membrane (3, 5). The peptide moiety of the monomer unit is assembled stepwise by the successive additions of L-alanine, D-glutamic acid, meso-diaminopimelic acid or L-lysine, and D-alanyl-D-alanine to UDP-N-acetylmuramic acid (UDP-MurNAc). These steps are catalyzed by specific peptide synthetases (ligases), which are designated as MurC, MurD, MurE, and MurF, respectively, all participating in non-ribosomal peptide bond for...

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Phosphinate Inhibitors of UDP‐N‐Acetylmuramoyl‐L‐Alanyl‐D‐Glutamate: L‐Lysine Ligase (MurE)

Cited by 34 publications

References 14 publications

The biology of Mur ligases as an antibacterial target

The biology of Mur ligases as an antibacterial target

Structural and Functional Characterization of Enantiomeric Glutamic Acid Derivatives as Potential Transition State Analogue Inhibitors of MurD Ligase

The MurC Ligase Essential for Peptidoglycan Biosynthesis Is Regulated by the Serine/Threonine Protein Kinase PknA in Corynebacterium glutamicum

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