ArticleBiochemistry2013
Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Staphylococcus aureus exploits lipoic acid salvage to combat host oxidative stress.Cell reports · 2025Article
- Indazole to 2-Cyanoindole Scaffold Progression for Mycobacterial Lipoamide Dehydrogenase Inhibitors Achieves Extended Target Residence Time and Improved Antibacterial Activity.Angewandte Chemie (International ed. in English) · 2024Article
- Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease.Sub-cellular biochemistry · 2024Review
- Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions.ACS infectious diseases · 2021Article
- Pyruvate dehydrogenase complex-enzyme 2, a new target for Listeria spp. detection identified using combined phage display technologies.Scientific reports · 2020Article
- Biology of antimicrobial resistance and approaches to combat it.Science translational medicine · 2020Review
- FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function.Journal of clinical medicine · 2019Article
- Dynamic Relay of Protein-Bound Lipoic Acid in Staphylococcus aureus.Journal of bacteriology · 2019Article
- Increased flexibility in the use of exogenous lipoic acid by Staphylococcus aureus.Molecular microbiology · 2018Article
- Kunkel Lecture: Fundamental immunodeficiency and its correction.The Journal of experimental medicine · 2017Review
- Global Kinetic Analysis of Mammalian E3 Reveals pH-dependent NAD+/NADH Regulation, Physiological Kinetic Reversibility, and Catalytic Optimum.The Journal of biological chemistry · 2016Article
- Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors.Journal of medicinal chemistry · 2015Article
- Stressed mycobacteria use the chaperone ClpB to sequester irreversibly oxidized proteins asymmetrically within and between cells.Cell host & microbe · 2015Article
- Mycobacterium tuberculosis metabolism.Cold Spring Harbor perspectives in medicine · 2014Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors.
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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.