Benzothioxalone derivatives as novel inhibitors of UDP-N-acetylglucosamine enolpyruvyl transferases (MurA and MurZ)

Miller, Keith; Dunsmore, Colin J.; Leeds, Jennifer A.; Patching, Simon G.; Sachdeva, Meena; Blake, Katy L.; Stubbings, Will; Simmons, Katie J.; Henderson, Peter J. F.; Angeles, Joe De Los; Fishwick, Colin W. G.; Chopra, Ian

doi:10.1093/jac/dkq349

Cited by 22 publications

(19 citation statements)

References 13 publications

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“…During MD simulations, the main hydrogen interactions proposed by molecular docking were maintained, and the key interactions with Lys22, Arg93, and Ser121 residues were also observed during the MD simulations. These residues (or equivalent residues in other MurA enzymes) are essential for the enzymatic catalysis and can be essential in enzymatic inhibition . In addition to these interactions, we have identified other important interactions with the residues Asp308 and Asn333 that may represent a new form of the inhibition of MurA, similar to that obtained by Eschenburg and co‐workers, where a derivative of 5‐sulfonoxy‐anthranilic acid inhibited MurA suspending the induced fit mechanism …”

Section: Resultssupporting

confidence: 77%

Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

et al. 2016

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UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is one of the key enzymes involved in peptidoglycan biosynthesis. The peptide HESFWYLPHQSY (called PEP 1354) is an inhibitor of MurA with an IC value of 200 μm. In this article, we have used the FlexPepDock ab-initio protocol from the Rosetta program homology modeling and molecular dynamics simulations to analyze, for the first time, the interaction of the PEP 1354 peptide with MurA enzyme from Pseudomonas aeruginosa (MurA-PA). Our modeling results suggest that the peptide binds to the same active site as the natural substrate UDP-N-acetylglucosamine (UNAG). Additionally, the MurA-peptide complex revealed that the peptide seems to prevent the closure of the Pro114-123 loop and, consequently, the open-closed transition of the MurA structure.

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Section: Resultssupporting

confidence: 77%

Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

et al. 2016

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“…Interestingly, the mutation changed the cysteine residue at position 115, which interacts with pep. The 115 residue has been actively investigated for implications in drug discovery (Bachelier et al, 2006;Barbosa et al, 2002;Baum et al, 2001;Couce et al, 2012;Desai and Miller, 2010;Dunsmore et al, 2008;Francisco et al, 2004;Kim et al, 1996;Miller et al, 2010;Xu et al, 2006). The above shifts in flux appeared to simultaneously increase flux through lower glycolysis (i.e., increased flux through ED) to increase the levels of lower glycolytic intermediates and generation of ATP and redox equivalents while minimizing glycolytic flux that would commit 1 mol of glucose to methylglyoxal generation.…”

Section: Additional Systematic Decoupling Of Pep Enzymatic Reactionsmentioning

confidence: 99%

Adaptation to the coupling of glycolysis to toxic methylglyoxal production in tpiA deletion strains of Escherichia coli requires synchronized and counterintuitive genetic changes

McCloskey

Sandberg

et al. 2018

Metabolic Engineering

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Methylglyoxal is a highly toxic metabolite that can be produced in all living organisms. Methylglyoxal was artificially elevated by removal of the tpiA gene from a growth optimized Escherichia coli strain. The initial response to elevated methylglyoxal and its toxicity was characterized, and detoxification mechanisms were studied using adaptive laboratory evolution. We found that: 1) Multi-omics analysis revealed biological consequences of methylglyoxal toxicity, which included attack on macromolecules including DNA and RNA and perturbation of nucleotide levels; 2) Counter-intuitive cross-talk between carbon starvation and inorganic phosphate signalling was revealed in the tpiA deletion strain that required mutations in inorganic phosphate signalling mechanisms to alleviate; and 3) The split flux through lower glycolysis depleted glycolytic intermediates requiring a host of synchronized and coordinated mutations in non-intuitive network locations in order to re-adjust the metabolic flux map to achieve optimal growth. Such mutations included a systematic inactivation of the Phosphotransferase System (PTS) and alterations in cell wall biosynthesis enzyme activity. This study demonstrated that deletion of major metabolic genes followed by ALE was a productive approach to gain novel insight into the systems biology underlying optimal phenotypic states.

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“…Inhibitory constants (IC 50 ) of the compounds tested for the inhibition of Escherichia coli Mur A and Mur B enzymes were collected from the literature. Literature data give sufficient information for building of QSAR models.…”

Section: Methodsmentioning

confidence: 99%

Application of SAR methods toward inhibition of bacterial peptidoglycan metabolizing enzymes

Drgan

Novič

2018

Journal of Chemometrics

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Structure activity relationship (SAR) methods are applied for a study of inhibition of peptidoglycan metabolizing enzymes, which could represent new antibacterial targets. In this study, we exploit experimental data of inhibition of Mur A and Mur B enzymes for classification of large set of chemicals. Based on inhibitory potency of compounds and their structures from the literature, we developed classification models for new, potential inhibitors of Mur A and Mur B enzymes. The best model for Mur A has the following performance measures for the validation set: 0.85, 0.75, and 0.80, for sensitivity, specificity, and normalized Matthews correlation coefficient, respectively. The same measures of the best Mur B model are 0.94, 0.75, and 0.86. Such models could represent valuable computational tools for theoretic predictions of compounds' activities against specific targets. Additionally, application of such models, like any other computational tools, significantly reduces time and costs in the early phase of drug design.

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Benzothioxalone derivatives as novel inhibitors of UDP-N-acetylglucosamine enolpyruvyl transferases (MurA and MurZ)

Cited by 22 publications

References 13 publications

Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

Computed insight into a peptide inhibitor preventing the induced fit mechanism of MurA enzyme from Pseudomonas aeruginosa

Adaptation to the coupling of glycolysis to toxic methylglyoxal production in tpiA deletion strains of Escherichia coli requires synchronized and counterintuitive genetic changes

Application of SAR methods toward inhibition of bacterial peptidoglycan metabolizing enzymes

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