ArticleAntimicrobial agents and chemotherapy2016
Characterization of DprE1-Mediated Benzothiazinone Resistance in Mycobacterium tuberculosis.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 55 citations in OpenAlex.
- Mechanism of the M. tuberculosis DprE1-DprE2 epimerase complex and inhibition by anti-tubercular drugs.Nature chemical biology · 2026Article
- Low-level BTZ-043 resistance inIJTLD open · 2025Article
- Disrupting tuberculosis pathogenesis by targeting DprE1 in cell wall biosynthesis: a structural dynamics perspective.Journal of computer-aided molecular design · 2025Article
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- Innovative Bedaquiline-Based Delivery Systems for Multidrug-Resistant Tuberculosis Treatment.Infectious disorders drug targets · 2025Review
- Novel Prodrug Strategies for the Treatment of Tuberculosis.Chemistry, an Asian journal · 2024Review
- An open-access dashboard to interrogate the genetic diversity of Mycobacterium tuberculosis clinical isolates.Scientific reports · 2024Article
- Synthesis, Activity, Toxicity, and In Silico Studies of New AntimycobacterialPharmaceuticals (Basel, Switzerland) · 2024Article
- Targeting decaprenylphosphoryl-β-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains.Bioinformatics and biology insights · 2024Article
- Synthesis and evaluation of triazole congeners of nitro-benzothiazinones potentially active against drug resistantRSC medicinal chemistry · 2022Article
- The Regulation of ManLAM-Related Gene Expression inInfection and drug resistance · 2022Article
- Recent Progress and Challenges for Drug-Resistant Tuberculosis Treatment.Pharmaceutics · 2021Review
- 8-cyanobenzothiazinone analogs with potent antitubercular activity.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2021Article
- Polarly Localized EccEJournal of bacteriology · 2020Article
- Synthesis, biological evaluation and molecular docking studies of 6-(4-nitrophenoxy)-1H-imidazo[4,5-b]pyridine derivatives as novel antitubercular agents: future DprE1 inhibitors.Chemistry Central journal · 2018Article
- Article
- Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis.Antimicrobial agents and chemotherapy · 2018Article
- The present state of the tuberculosis drug development pipeline.Current opinion in pharmacology · 2018Review
- Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1.Scientific reports · 2018Article
- Metabolism of SKLB-TB1001, a Potent Antituberculosis Agent, in Animals.Antimicrobial agents and chemotherapy · 2018Article
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Authors and funding
10 authors at 1 institution in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Benzothiazinones (BTZs) are a class of compounds found to be extremely potent against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains. The potency of BTZs is explained by their specificity for their target decaprenylphosphoryl-d-ribose oxidase (DprE1), in particular by covalent binding of the activated form of the compound to the critical cysteine 387 residue of the enzyme. To probe the role of C387, we used promiscuous site-directed mutagenesis to introduce other codons at this position into dprE1 of M. tuberculosis The resultant viable BTZ-resistant mutants were characterized in vitro, ex vivo, and biochemically to gain insight into the effects of these mutations on DprE1 function and on M. tuberculosis Five different mutations (C387G, C387A, C387S, C387N, and C387T) conferred various levels of resistance to BTZ and exhibited different phenotypes. The C387G and C387N mutations resulted in a lower growth rate of the mycobacterium on solid medium, which could be attributed to the significant decrease in the catalytic efficiency of the DprE1 enzyme. All five mutations rendered the mycobacterium less cytotoxic to macrophages. Finally, differences in the potencies of covalent and noncovalent DprE1 inhibitors in the presence of C387 mutations were revealed by enzymatic assays. As expected from the mechanism of action, the covalent inhibitor PBTZ169 only partially inhibited the mutant DprE1 enzymes compared to the near-complete inhibition with a noncovalent DprE1 inhibitor, Ty38c. This study emphasizes the importance of the C387 residue for DprE1 activity and for the killing action of covalent inhibitors such as BTZs and other recently identified nitroaromatic inhibitors.
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