ArticleThe Journal of antimicrobial chemotherapy2016
High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors.
Article in The Journal of antimicrobial chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- Assessing the threat ofAntimicrobial agents and chemotherapy · 2025Article
- Recent advances in small molecule LpxC inhibitors against gram-negative bacteria (2014-2024).Frontiers in microbiology · 2025Review
- Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives.Molecules (Basel, Switzerland) · 2023Review
- Article
- TP0586532, a non-hydroxamate LpxC inhibitor, has in vitro and in vivo antibacterial activities against Enterobacteriaceae.The Journal of antibiotics · 2022Article
- Antibiotic Therapy of Plague: A Review.Biomolecules · 2021Review
- 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
- Degradation of Components of the Lpt Transenvelope Machinery Reveals LPS-Dependent Lpt Complex Stability inFrontiers in molecular biosciences · 2021Article
- Essential Genes ofFrontiers in microbiology · 2021Article
- Dual Role ofAntimicrobial agents and chemotherapy · 2019Article
- Targeting Metalloenzymes for Therapeutic Intervention.Chemical reviews · 2019Review
- New Treatment Options against Carbapenem-ResistantAntimicrobial agents and chemotherapy · 2019Review
- Interplay of Klebsiella pneumoniaemSphere · 2018Article
- Structure, inhibition, and regulation of essential lipid A enzymes.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2017Review
- The Mla pathway is critical for Pseudomonas aeruginosa resistance to outer membrane permeabilization and host innate immune clearance.Journal of molecular medicine (Berlin, Germany) · 2017Article
- Article
- 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors.International journal of molecular sciences · 2017Article
- Generation and Validation of the iKp1289 Metabolic Model for Klebsiella pneumoniae KPPR1.The Journal of infectious diseases · 2017Article
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Authors and funding
12 authors at 5 institutions in 2 countries.
Funding
Abstract
objectivesInhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics.
methodsMICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively.
resultsLPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group.
conclusionsThese in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies.
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