ArticleBiochemistry2009
Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 11 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
11 citing papers in PubMed, 35 citations in OpenAlex.
- Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014-2024).Frontiers in microbiology · 2025Review
- Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity.Journal of medicinal chemistry · 2024Article
- Novel Hydroxamic Acids Containing Aryl-Substituted 1,2,4- or 1,3,4-Oxadiazole Backbones and an Investigation of Their Antibiotic Potentiation Activity.International journal of molecular sciences · 2023Article
- Uridine Derivatives: Synthesis, Biological Evaluation, and In Silico Studies as Antimicrobial and Anticancer Agents.Medicina (Kaunas, Lithuania) · 2023Article
- The Complex Structure of Protein AaLpxC fromMolecules (Basel, Switzerland) · 2021Article
- Hierarchical-Clustering, Scaffold-Mining Exercises and Dynamics Simulations for Effectual Inhibitors Against Lipid-A Biosynthesis ofCellular and molecular bioengineering · 2019Article
- Facile Solid-Phase Synthesis and Assessment of Nucleoside Analogs as Inhibitors of Bacterial UDP-Sugar Processing Enzymes.ACS chemical biology · 2018Article
- Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC.Cold Spring Harbor perspectives in medicine · 2016Review
- Control of lipopolysaccharide biosynthesis by FtsH-mediated proteolysis of LpxC is conserved in enterobacteria but not in all gram-negative bacteria.Journal of bacteriology · 2011Article
- Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold.Bioorganic & medicinal chemistry · 2011Article
- Challenges of antibacterial discovery.Clinical microbiology reviews · 2011Review
Corrections and comments
- Erratum issuedHangauer, Matthew J [added]
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A (endotoxin) biosynthesis in Gram-negative bacteria and is a validated antibiotic target. Although several previously described compounds bind to the unique acyl chain binding passage of LpxC with high affinity, strategies to target the enzyme's UDP-binding site have not been reported. Here the identification of a series of uridine-based LpxC inhibitors is presented. The most potent examined, 1-68A, is a pH-dependent, two-step, covalent inhibitor of Escherichia coli LpxC that competes with UDP to bind the enzyme in the first step of inhibition. Compound 1-68A exhibits a K(I) of 54 muM and a maximal rate of inactivation (k(inact)) of 1.7 min(-1) at pH 7.4. Dithiothreitol, glutathione and the C207A mutant of E. coli LpxC prevent the formation of a covalent complex by 1-68A, suggesting a role for Cys-207 in inhibition. The inhibitory activity of 1-68A and a panel of synthetic analogues identified moieties necessary for inhibition. 1-68A and a 2-dehydroxy analogue, 1-68Aa, inhibit several purified LpxC orthologues. These compounds may provide new scaffolds for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.