2-Aminotetralones: Novel inhibitors of MurA and MurZ

Dunsmore, Colin J.; Miller, Keith; Blake, Katy L.; Patching, Simon G.; Henderson, Peter J. F.; Garnett, James A.; Stubbings, Will; Phillips, Simon E. V.; Palestrant, Deborah; Angeles, Joseph De Los; Leeds, Jennifer A.; Chopra, Ian; Fishwick, Colin W. G.

doi:10.1016/j.bmcl.2008.01.089

Cited by 34 publications

(24 citation statements)

References 17 publications

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“…Also, the increasing effort to identify novel specific inhibitors of these essential and conserved enzyme targets (18,42,44,53,56) may help advance our understanding of the role of PG in this important human pathogen.…”

Section: Discussionmentioning

confidence: 99%

Functional and Biochemical Analysis of theChlamydia trachomatisLigase MurE

et al. 2009

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Chlamydiae are unusual obligately intracellular bacteria that do not synthesize detectable peptidoglycan. However, they possess genes that appear to encode products with peptidoglycan biosynthetic activity. Bioinformatic analysis predicts that chlamydial MurE possesses UDP-MurNAc-L-Ala-D-Glu:meso-diaminopimelic acid (UDP-MurNAc-L-Ala-D-Glu:meso-A 2 pm) ligase activity. Nevertheless, there are no experimental data to confirm this hypothesis. In this paper we demonstrate that the murE gene from Chlamydia trachomatis is capable of complementing a conditional Escherichia coli mutant impaired in UDP-MurNAc-L-Ala-D-Glu:meso-A 2 pm ligase activity. Recombinant MurE from C. trachomatis (MurE Ct ) was overproduced in and purified from E. coli in order to investigate its kinetic parameters in vitro. By use of UDP-MurNAc-L-Ala-D-Glu as the nucleotide substrate, MurE Ct demonstrated ATP-dependent meso-A 2 pm ligase activity with pH and magnesium ion optima of 8.6 and 30 mM, respectively. Other amino acids (meso-lanthionine, the LL and DD isomers of A 2 pm, D-lysine) were also recognized by MurE Ct. However, the activities for these amino acid substrates were weaker than that for meso-A 2 pm. The specificity of MurE Ct for three possible C. trachomatis peptidoglycan nucleotide substrates was also determined in order to deduce which amino acid might be present at the first position of the UDP-MurNAc-pentapeptide. Relative k cat /K m ratios for UDP-MurNAc-L-Ala-D-Glu, UDPMurNAc-L-Ser-D-Glu, and UDP-MurNAc-Gly-D-Glu were 100, 115, and 27, respectively. Our results are consistent with the synthesis in chlamydiae of a UDP-MurNAc-pentapeptide in which the third amino acid is meso-A 2 pm. However, due to the lack of specificity of MurE Ct for nucleotide substrates in vitro, it is not obvious which amino acid is present at the first position of the pentapeptide.

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Section: Discussionmentioning

confidence: 99%

Functional and Biochemical Analysis of theChlamydia trachomatisLigase MurE

et al. 2009

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“…Substantial efforts have been directed toward the discovery of antibacterial inhibitors of early-stage CWB, mediated by the Mur enzymes (1,2,12) (Fig. 1).…”

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confidence: 99%

Transcriptional Signature following Inhibition of Early-Stage Cell Wall Biosynthesis in Staphylococcus aureus

O’Neill

Lindsay

Gould

et al. 2009

Antimicrob Agents Chemother

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“…In fact, Asp-305 must be responsible for the final proton abstraction from the C-3 atom of the PEP moiety required for the elimination of inorganic phosphate [57]. Other inhibitors of MurA based around a 2-aminotetralone motif [58] and other electrophilic natural products such as terreic acid [59] and cnicin [60] are covalent MurA inhibitors that essentially compete with PEP for reaction with Cys-115 via a covalent mode of action involving the Cys115 thiol group of MurA.…”

Section: Methodsmentioning

confidence: 99%

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

et al. 2015

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SUMMARY Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.

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2-Aminotetralones: Novel inhibitors of MurA and MurZ

Cited by 34 publications

References 17 publications

Functional and Biochemical Analysis of theChlamydia trachomatisLigase MurE

Functional and Biochemical Analysis of theChlamydia trachomatisLigase MurE

Transcriptional Signature following Inhibition of Early-Stage Cell Wall Biosynthesis in Staphylococcus aureus

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

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