Structure-Based Inhibitors Exhibit Differential Activities against<i>Helicobacter pylori</i>and<i>Escherichia coli</i>Undecaprenyl Pyrophosphate Synthases

Kuo, C.J.; Guo, Rey‐Ting; Lu, I-Lin; Liu, Hun‐Ge; Wu, Su-Ying; Ko, Tzu‐Ping; Wang, Andrew H.-J.; Liang, Po‐Huang

doi:10.1155/2008/841312

Cited by 32 publications

(34 citation statements)

References 25 publications

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“…1 It is possible that such inhibitors may not affect other commensal bacteria, including B. fragilis . However, no other UPPS enzymes from bacteria have been isolated until now.…”

Section: Discussionmentioning

confidence: 99%

“…1, 2 However, the production of these complex oligosaccharides is difficult to screen in vitro . One of the major drawbacks to studying sugar biosynthetic systems is the reliance of prokaryotic organisms on the 55-carbon isoprenoid bactoprenyl monophosphate (BP).…”

Section: Introductionmentioning

confidence: 99%

“…21, 22 Recently, it has been shown that UPPS from the pathogenic microbe Heliobacter pylori can be affected by an inhibitor that does not influence the activity of a similar E. coli UPPS. 1 …”

Section: Introductionmentioning

confidence: 99%

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Chemoenzymatic synthesis of an isoprenoid phosphate tool for the analysis of complex bacterial oligosaccharide biosynthesis

Lujan

Stanziale

Mostafavi

et al. 2012

Carbohydrate Research

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Undecaprenyl Pyrophosphate Synthase (UPPS) is a key enzyme that catalyzes the production of bactoprenols, which act as membrane anchors for the assembly of complex bacterial oligosaccharides. One of the major hurdles in understanding the assembly of oligosaccharide assembly is a lack of chemical tools to study this process, since bactoprenols and the resulting isoprenoid-linked oligosaccharides lack handles or chromophores for use in pathway analysis. Here we describe the isolation of a new UPPS from the symbiotic microorganism Bacteroides fragilis, a key species in the human microbiome. The protein was purified to homogeneity and utilized to accept a chromophore containing farnesyl diphosphate analogue as a substrate. The analogue was utilized by the enzyme and resulted in a bactoprenyl diphosphate product with an easy to monitor tag associated with it. Furthermore, the diphosphate is shown to be readily converted to monophosphate using a common molecular biology reagent. This monophosphate product allowed for the investigation of complex oligosaccharide biosynthesis, and was used to probe the activity of glycosyltransferases involved in the well characterized Campylobacter jejuni N-linked protein glycosylation. Novel reagents similar to this will provide key tools for the study of uncharacterized oligosaccharide assemblies, and open the possibility for the development of rapid screening methodology for these biosynthetic systems.

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“…1 It is possible that such inhibitors may not affect other commensal bacteria, including B. fragilis . However, no other UPPS enzymes from bacteria have been isolated until now.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chemoenzymatic synthesis of an isoprenoid phosphate tool for the analysis of complex bacterial oligosaccharide biosynthesis

Lujan

Stanziale

Mostafavi

et al. 2012

Carbohydrate Research

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“…1). Formation of 4 is catalyzed by the enzyme undecaprenyl diphosphate synthase (UPPS), and several UPPS inhibitors have been reported (3)(4)(5)(6)(7)(8)(9)(10). UPP is then hydrolyzed to the monophosphate, which is next converted to lipid I and lipid II, leading to formation of cell wall peptidoglycan ( Fig.…”

mentioning

confidence: 99%

Antibacterial drug leads targeting isoprenoid biosynthesis

Zhu

Zhang

Sinko³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

157

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With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC) 90 ∼0.25 μg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.drug discovery | in silico high-throughput screening | peptidoglycan | protein structure

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“…C 55 -P also serves as a carrier in the synthesis of peptidoglycan as well as various other cell wall components such as wall teichoic acids, lipopolysaccharide, and O-antigens (5-7). Considerable effort has been devoted to the identification of selective UppS inhibitors as lead compounds for antibiotic development (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Reducing the Level of Undecaprenyl Pyrophosphate Synthase Has Complex Effects on Susceptibility to Cell Wall Antibiotics

Lee

Helmann

2013

Antimicrob Agents Chemother

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Undecaprenyl pyrophosphate synthase (UppS) catalyzes the formation of the C 55 lipid carrier (UPP) that is essential for bacterial peptidoglycan biosynthesis. We selected here a vancomycin (VAN)-resistant derivative of Bacillus subtilis W168 that contains a single-point mutation in the ribosome-binding site of the uppS gene designated uppS1. Genetic reconstruction experiments demonstrate that the uppS1 allele is sufficient to confer low-level VAN resistance and causes reduced UppS translation. The decreased level of UppS renders B. subtilis slightly more susceptible to many late-acting cell wall antibiotics, including ␤-lactams, but significantly more resistant to fosfomycin and D-cycloserine, antibiotics that interfere with the very early steps of cell wall synthesis. We further show that the uppS1 allele leads to slightly elevated expression of the M regulon, possibly helping to compensate for the stress caused by a decrease in UPP levels. Notably, the uppS1 mutation increases resistance to VAN, fosfomycin, and D-cycloserine in wild-type cells, but this effect is greatly reduced or eliminated in a sigM mutant background. Our findings suggest that, although UppS is an attractive antibacterial target, incomplete inhibition of UppS function may lead to increased resistance to some cell wall-active antibiotics.

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Structure-Based Inhibitors Exhibit Differential Activities againstHelicobacter pyloriandEscherichia coliUndecaprenyl Pyrophosphate Synthases

Cited by 32 publications

References 25 publications

Chemoenzymatic synthesis of an isoprenoid phosphate tool for the analysis of complex bacterial oligosaccharide biosynthesis

Chemoenzymatic synthesis of an isoprenoid phosphate tool for the analysis of complex bacterial oligosaccharide biosynthesis

Antibacterial drug leads targeting isoprenoid biosynthesis

Reducing the Level of Undecaprenyl Pyrophosphate Synthase Has Complex Effects on Susceptibility to Cell Wall Antibiotics

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