3,5-Dioxopyrazolidines, Novel Inhibitors of UDP-
            <i>N</i>
            - Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria

Yang, Youjun; Severin, Anatoly; Chopra, Rajiv; Krishnamurthy, Girija; Singh, Guy; Hu, William; Keeney, David; Svenson, Kristine; Petersen, Peter J.; Labthavikul, Pornpen; Shlaes, David M.; Rasmussen, Beth A.; Failli, Amedeo; Shumsky, Jay S.; Kutterer, Kristina M. K.; Gilbert, Adam M.; Mansour, Tarek S.

doi:10.1128/aac.50.2.556-564.2006

Cited by 65 publications

(47 citation statements)

References 51 publications

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“…These campaigns all yielded sets of compounds with various spectra of target inhibition, from inhibiting a single target (among MurA to MurF) to inhibiting sets of one, two, three, or four enzymes. Some were shown to inhibit synthesis of soluble peptidoglycan in whole cells, but no other MMS inhibition was measured (119,395). The lack of this negative control lowers the value of (396) Imidazoles (154) Thiopyridines (214) Aminopyridines (177,258,294) and -K) the finding.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 96%

“…A number of synthetic projects undertaken by the Wyeth group (12,119,201,212,234,395) were directed toward finding inhibitors of multiple enzymatic steps in the Mur pathway, with the idea that hitting multiple targets would lessen ultimate resistance selection. For many of these, the lead compound was discovered in a "one-pot" MurA-to-MurF screen (234), probably similar to those of Merck and Versicor.…”

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

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Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,156

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 96%

Section: Murb To Murf Enzymes As Antibacterial Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,156

961

View full text Add to dashboard Cite

show abstract

“…The subsequent steps in the pathway are entirely dependent on the MurB product UDP-MurNAc for completion and delivery of peptidoglycan monomer units to actively growing regions of the bacterial cell wall. Due to its importance in peptidoglycan biosynthesis, the MurB enzyme has been the subject of a number of target-based drug design efforts (8,18,21,36,39,69).…”

mentioning

confidence: 99%

Evaluation of the metS and murB Loci for Antibiotic Discovery Using Targeted Antisense RNA Expression Analysis in Bacillus anthracis

Kedar

Brown-Driver

Reyes

et al. 2007

Antimicrob Agents Chemother

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The biowarfare-relevant bacterial pathogen Bacillus anthracis contains two paralogs each of the metS and murB genes, which encode the important antibiotic target functions methionyl-tRNA synthetase and UDP-Nacetylenolpyruvoylglucosamine reductase, respectively. Empirical screens were conducted to detect and characterize gene fragments of each of these four genes that could cause growth reduction of B. anthracis when inducibly expressed from a plasmid-borne promoter. Numerous such gene fragments that were overwhelmingly in the antisense orientation were identified for the metS1 and murB2 alleles, while no such orientation bias was seen for the metS2 and murB1 alleles. Gene replacement mutagenesis was used to confirm the essentiality of the metS1 and murB2 alleles, and the nonessentiality of the metS2 and murB1 alleles, for vegetative growth. Induced transcription of RNA from metS1 and murB2 antisense-oriented gene fragments resulted in specific reduction of mRNA of their cognate genes. Attenuation of MetS1 enzyme expression hypersensitized B. anthracis cells to a MetS-specific antimicrobial compound but not to other antibiotics that affect cell wall assembly, fatty acid biosynthesis, protein translation, or DNA replication. Antisense-dependent reduction of MurB2 enzyme expression caused hypersensitivity to beta-lactam antibiotics, a synergistic response that has also been noted for the MurA-specific antibiotic fosfomycin. These experiments form the basis of mode-ofaction detection assays that can be used in the discovery of novel MetS-or MurB-specific antibiotic drugs that are effective against B. anthracis or other gram-positive bacterial pathogens.

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“…However, no activity against E. coli and PRSP was detected in the presence of 4% BSA, while vancomycin and fosfomycin MICs were not affected by the addition of BSA [93].…”

Section: Inhibitors Of Murbmentioning

confidence: 56%

Development of Novel Inhibitors Targeting Intracellular Steps of Peptidoglycan Biosynthesis

Kotnik¹,

Anderluh²,

Prezelj³

2007

CPD

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The widespread emergence of pathogenic bacterial strains with resistance to antibiotics is becoming a serious threat to public health. Continuous development of novel antibacterials therefore remains one of the biggest challenges to science and unmet needs in the clinics. The biosynthetic pathway of bacterial peptidoglycan, an essential building block of cell walls, has been well studied and appears to be a rich source of attractive enzyme targets for new antibacterials. We have therefore reviewed the intracellular part of peptidoglycan biosynthesis, including the enzymes GlmS, GlmM, GlmU for formation of UDP-GlcNAc, subsequent pentapeptide synthesis by MurA-MurF, and its connection to lipid carrier by MraY and MurG. Naturally occurring inhibitors and the development of low-molecular weight inhibitors of the intracellular part of peptidoglycan synthesis are presented.

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3,5-Dioxopyrazolidines, Novel Inhibitors of UDP- N - Acetylenolpyruvylglucosamine Reductase (MurB) with Activity against Gram-Positive Bacteria

Cited by 65 publications

References 51 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

Evaluation of the metS and murB Loci for Antibiotic Discovery Using Targeted Antisense RNA Expression Analysis in Bacillus anthracis

Development of Novel Inhibitors Targeting Intracellular Steps of Peptidoglycan Biosynthesis

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