ArticleThe Journal of biological chemistry2003
Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis.
Article in The Journal of biological chemistry, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers, 1 of them a synthesis that pooled it.
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Who cites it
64 citing papers in PubMed, 1 synthesis or guideline pooled it, 164 citations in OpenAlex.
- Transcriptional Profiling of Mycobacterium tuberculosis Exposed to In Vitro Lysosomal Stress.Infection and immunity · 2016Pooled it
- The Flexible Peripheral Segments Modulate the Catalytic Activity of the FAD-Containing Monooxygenase EthA fromBiomolecules · 2026Article
- Targeting opportunities presented by the pyrimidine biosynthesis pathway in Mycobacterium tuberculosis: a brief review.Biochemical Society transactions · 2026Review
- Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Urea-sugar and thiourea-sugar diastereomers: synthesis, crystal structure and biological activities.Future medicinal chemistry · 2025Article
- Development ofMini reviews in medicinal chemistry · 2025Review
- Novel Prodrug Strategies for the Treatment of Tuberculosis.Chemistry, an Asian journal · 2024Review
- Novel Thiourea Ligands-Synthesis, Characterization and Preliminary Study on Their Coordination Abilities.Molecules (Basel, Switzerland) · 2024Article
- Genetic and chemical control of tuberculostearic acid production inMicrobiology spectrum · 2024Article
- Metabolic Rewiring ofMetabolites · 2024Review
- Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.Current medicinal chemistry · 2024Review
- Genetic Underpinnings of Carotenogenesis and Light-Induced Transcriptome Remodeling in the Opportunistic PathogenPathogens (Basel, Switzerland) · 2023Article
- Recent trends in chemistry, structure, and various applications of 1-acyl-3-substituted thioureas: a detailed review.RSC advances · 2022Review
- Advances in Key Drug Target Identification and New Drug Development for Tuberculosis.BioMed research international · 2022Review
- Article
- Lipid and fatty acid metabolism in trypanosomatids.Microbial cell (Graz, Austria) · 2021Review
- Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding.PLoS pathogens · 2021Article
- Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives.International journal of molecular sciences · 2021Article
- Metabolic Versatility ofMetabolites · 2021Review
- Continuous-Flow Synthesis of Thioureas, Enabled by Aqueous Polysulfide Solution.Molecules (Basel, Switzerland) · 2021Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
The thiourea isoxyl (thiocarlide; 4,4'-diisoamyloxydiphenylthiourea) is known to be an effective anti-tuberculosis drug, active against a range of multidrug-resistant strains of Mycobacterium tuberculosis and has been used clinically. Little was known of its mode of action. We now demonstrate that isoxyl results in a dose-dependent decrease in the synthesis of oleic and, consequently, tuberculostearic acid in M. tuberculosis with complete inhibition at 3 microg/ml. Synthesis of mycolic acid was also affected. The anti-bacterial effect of isoxyl was partially reversed by supplementing growth medium with oleic acid. The specificity of this inhibition pointed to a Delta9-stearoyl desaturase as the drug target. Development of a cell-free assay for Delta9-desaturase activity allowed direct demonstration of the inhibition of oleic acid synthesis by isoxyl. Interestingly, sterculic acid, a known inhibitor of Delta9-desaturases, emulated the effect of isoxyl on oleic acid synthesis but did not affect mycolic acid synthesis, demonstrating the lack of a relationship between the two effects of the drug. The three putative fatty acid desaturases in the M. tuberculosis genome, desA1, desA2, and desA3, were cloned and expressed in Mycobacterium bovis BCG. Cell-free assays and whole cell labeling demonstrated increased Delta9-desaturase activity and oleic acid synthesis only in the desA3-overexpressing strain and an increase in the minimal inhibitory concentration for isoxyl, indicating that DesA3 is the target of the drug. These results validate membrane-bound Delta9-desaturase, DesA3, as a new therapeutic target, and the thioureas as anti-tuberculosis drugs worthy of further development.
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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.