ArticleACS chemical biology2014
Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC.
Article in ACS chemical biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 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
20 citing papers in PubMed, 32 citations in OpenAlex.
- Discovery and Optimization of Novel Nonhydroxamate LpxC Inhibitors for the Treatment of Multidrug-Resistant Gram-Negative Infections.Journal of medicinal chemistry · 2026Article
- Synthesis, Biological Evaluation, and Molecular Docking Studies of 2r,3t,4c-Configured C-Furanosidic LpxC Inhibitors.Archiv der Pharmazie · 2026Article
- 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
- Properties and biotechnological applications of microbial deacetylase.Applied microbiology and biotechnology · 2023Review
- Indole-based LpxC (UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosaminedeacetylase) inhibitors for3 Biotech · 2023Article
- Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.Journal of medicinal chemistry · 2022Article
- Article
- Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.Accounts of chemical research · 2021Review
- Regulation of the First Committed Step in Lipopolysaccharide Biosynthesis Catalyzed by LpxC Requires the Essential Protein LapC (YejM) and HslVU Protease.International journal of molecular sciences · 2020Article
- Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
- Structure, inhibition, and regulation of essential lipid A enzymes.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2017Review
- Chlamydia spp. development is differentially altered by treatment with the LpxC inhibitor LPC-011.BMC microbiology · 2017Article
- High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors.The Journal of antimicrobial chemotherapy · 2016Article
- The Power of Asymmetry: Architecture and Assembly of the Gram-Negative Outer Membrane Lipid Bilayer.Annual review of microbiology · 2016Review
- Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC.Cold Spring Harbor perspectives in medicine · 2016Review
- LpxC Inhibitors: Design, Synthesis, and Biological Evaluation of Oxazolidinones as Gram-negative Antibacterial Agents.ACS medicinal chemistry letters · 2016Article
- Endless Resistance. Endless Antibiotics?MedChemComm · 2016Article
- Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.ACS medicinal chemistry letters · 2014Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent LpxC inhibitors with a variety of chemical scaffolds and distinct antibiotic profiles. The vast majority of these compounds, including the nanomolar inhibitors L-161,240 and BB-78485, are highly effective in suppressing the activity of Escherichia coli LpxC (EcLpxC) but not divergent orthologs such as Pseudomonas aeruginosa LpxC (PaLpxC) in vitro. The molecular basis for such promiscuous inhibition of EcLpxC has remained poorly understood. Here, we report the crystal structure of EcLpxC bound to L-161,240, providing the first molecular insight into L-161,240 inhibition. Additionally, structural analysis of the EcLpxC/L-161,240 complex together with the EcLpxC/BB-78485 complex reveals an unexpected backbone flipping of the Insert I βa-βb loop in EcLpxC in comparison with previously reported crystal structures of EcLpxC complexes with l-threonyl-hydroxamate-based broad-spectrum inhibitors. Such a conformational switch, which has only been observed in EcLpxC but not in divergent orthologs such as PaLpxC, results in expansion of the active site of EcLpxC, enabling it to accommodate LpxC inhibitors with a variety of head groups, including compounds containing single (R- or S-enantiomers) or double substitutions at the neighboring Cα atom of the hydroxamate warhead group. These results highlight the importance of understanding inherent conformational plasticity of target proteins in lead optimization.
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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.