ArticleBiochemistry2015
Mechanism of MenE inhibition by acyl-adenylate analogues and discovery of novel antibacterial agents.
Article in Biochemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 33 citations in OpenAlex.
- Biological characteristics of a menadione-dependent Staphylococcus aureus small colony variant (SCV) from bovine mastitis and heme promotion of biofilm formation.Archives of microbiology · 2026Article
- An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.PLoS pathogens · 2024Article
- Allosteric inhibition ofPhilosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Indane-1,3-Dione: From Synthetic Strategies to Applications.Molecules (Basel, Switzerland) · 2022Review
- Structure and activity of the DHNA Coenzyme-A Thioesterase from Staphylococcus aureus providing insights for innovative drug development.Scientific reports · 2022Article
- Structural approaches to pathway-specific antimicrobial agents.Translational research : the journal of laboratory and clinical medicine · 2020Review
- Targeting adenylate-forming enzymes with designed sulfonyladenosine inhibitors.The Journal of antibiotics · 2019Review
- Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE.Biochemistry · 2019Article
- Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery.Pathogens (Basel, Switzerland) · 2018Review
- Menaquinone biosynthesis inhibition: a review of advancements toward a new antibiotic mechanism.RSC advances · 2018Review
- A Novel Small-Molecule Inhibitor of themBio · 2017Article
- Novel long-chain compounds with both immunomodulatory and MenA inhibitory activities against Staphylococcus aureus and its biofilm.Scientific reports · 2017Article
- Stereoselective Synthesis, Docking, and Biological Evaluation of Difluoroindanediol-Based MenE Inhibitors as Antibiotics.Organic letters · 2016Article
- Designed Small-Molecule Inhibitors of the Anthranilyl-CoA Synthetase PqsA Block Quinolone Biosynthesis in Pseudomonas aeruginosa.ACS chemical biology · 2016Article
- Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes.Bioorganic & medicinal chemistry letters · 2016Article
- A Methyl 4-Oxo-4-phenylbut-2-enoate withACS infectious diseases · 2016Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
MenE is an o-succinylbenzoyl-CoA (OSB-CoA) synthetase in the bacterial menaquinone biosynthesis pathway and is a promising target for the development of novel antibacterial agents. The enzyme catalyzes CoA ligation via an acyl-adenylate intermediate, and we have previously reported tight-binding inhibitors of MenE based on stable acyl-sulfonyladenosine analogues of this intermediate, including OSB-AMS (1), which has an IC50 value of ≤25 nM for Escherichia coli MenE. Herein, we show that OSB-AMS reduces menaquinone levels in Staphylococcus aureus, consistent with its proposed mechanism of action, despite the observation that the antibacterial activity of OSB-AMS is ∼1000-fold lower than the IC50 for enzyme inhibition. To inform the synthesis of MenE inhibitors with improved antibacterial activity, we have undertaken a structure-activity relationship (SAR) study stimulated by the knowledge that OSB-AMS can adopt two isomeric forms in which the OSB side chain exists either as an open-chain keto acid or a cyclic lactol. These studies revealed that negatively charged analogues of the keto acid form bind, while neutral analogues do not, consistent with the hypothesis that the negatively charged keto acid form of OSB-AMS is the active isomer. X-ray crystallography and site-directed mutagenesis confirm the importance of a conserved arginine for binding the OSB carboxylate. Although most lactol isomers tested were inactive, a novel difluoroindanediol inhibitor (11) with improved antibacterial activity was discovered, providing a pathway toward the development of optimized MenE inhibitors in the future.
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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.