ArticleThe Journal of biological chemistry2014
Rational design of broad spectrum antibacterial activity based on a clinically relevant enoyl-acyl carrier protein (ACP) reductase inhibitor.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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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.
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Who cites it
29 citing papers in PubMed, 63 citations in OpenAlex.
- Underexplored Ligand-Binding Features of FabI From Staphylococcus aureus and Escherichia coli: A Comparative Pharmacophoric Modeling and Surface Mapping Approach.ChemMedChem · 2026Article
- Bacterial Acyl Carrier Proteins Are a Cytoplasmic Target for Different Cationic Antimicrobial and Antibiofilm Peptides.International journal of molecular sciences · 2026Article
- Treatment of MRSA Infection: Where are We?Current medicinal chemistry · 2024Review
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- A broad inhibitor of acyl-acyl carrier protein synthetases.Biochemistry and biophysics reports · 2023Article
- Hydrothermal Synthesis of Fe-Doped Cadmium Oxide Showed Bactericidal Behavior and Highly Efficient Visible Light Photocatalysis.ACS omega · 2023Article
- Targeted Isolation of Antibiotic Brominated Alkaloids from the Marine SpongeMarine drugs · 2022Article
- Enhanced Photocatalytic Degradation with Sustainable CaO Nanorods Doped with Ce and Cellulose Nanocrystals: In Silico Molecular Docking Studies.ACS omega · 2022Article
- Development of Multi-concentration Cu:Ag Bimetallic Nanoparticles as a Promising Bactericidal for Antibiotic-Resistant Bacteria as Evaluated with Molecular Docking Study.Nanoscale research letters · 2021Article
- A Long Residence Time Enoyl-Reductase Inhibitor Explores an Extended Binding Region with Isoenzyme-Dependent Tautomer Adaptation and Differential Substrate-Binding Loop Closure.ACS infectious diseases · 2021Article
- Synthesis of an acyl-acyl carrier protein synthetase inhibitor to study fatty acid recycling.Scientific reports · 2020Article
- Structural approaches to pathway-specific antimicrobial agents.Translational research : the journal of laboratory and clinical medicine · 2020Review
- Ligand- and Structure-Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence.ChemMedChem · 2019Article
- Multiomics Assessment of Gene Expression in a Clinical Strain of CTX-M-15-Producing ST131Frontiers in microbiology · 2019Article
- Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques.Bioorganic & medicinal chemistry letters · 2018Article
- Better living through chemistry: Addressing emerging antibiotic resistance.Experimental biology and medicine (Maywood, N.J.) · 2018Review
- Clinical Relevance of Type II Fatty Acid Synthesis Bypass in Staphylococcus aureus.Antimicrobial agents and chemotherapy · 2017Article
- Rationalizing the Binding Kinetics for the Inhibition of the Burkholderia pseudomallei FabI1 Enoyl-ACP Reductase.Biochemistry · 2017Article
- Transient In Vivo Resistance Mechanisms of Burkholderia pseudomallei to Ceftazidime and Molecular Markers for Monitoring Treatment Response.PLoS neglected tropical diseases · 2017Article
- Environmental fatty acids enable emergence of infectious Staphylococcus aureus resistant to FASII-targeted antimicrobials.Nature communications · 2016Article
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 2 countries.
Funding
Abstract
Determining the molecular basis for target selectivity is of particular importance in drug discovery. The ideal antibiotic should be active against a broad spectrum of pathogenic organisms with a minimal effect on human targets. CG400549, a Staphylococcus-specific 2-pyridone compound that inhibits the enoyl-acyl carrier protein reductase (FabI), has recently been shown to possess human efficacy for the treatment of methicillin-resistant Staphylococcus aureus infections, which constitute a serious threat to human health. In this study, we solved the structures of three different FabI homologues in complex with several pyridone inhibitors, including CG400549. Based on these structures, we rationalize the 65-fold reduced affinity of CG400549 toward Escherichia coli versus S. aureus FabI and implement concepts to improve the spectrum of antibacterial activity. The identification of different conformational states along the reaction coordinate of the enzymatic hydride transfer provides an elegant visual depiction of the relationship between catalysis and inhibition, which facilitates rational inhibitor design. Ultimately, we developed the novel 4-pyridone-based FabI inhibitor PT166 that retained favorable pharmacokinetics and efficacy in a mouse model of S. aureus infection with extended activity against Gram-negative and mycobacterial organisms.
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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.