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Cited by 48Tuberculosis Research and EpidemiologyPhenothiazines and Benzothiazines Synthesis and ActivitiesSynthesis and Biological Evaluation

Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis

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Gao, Chao, Peng, Cuiting, Shi, Yaojie, You, Xinyu, Ran, Kai, Xiong, Lu, Ye, Ting-hong, Zhang, Lidan +6 more·2016·Scientific Reports
DOI 10.1038/srep29717PMC PMC4942819
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Abstract

New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.

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  • The effectiveness activity profile of ethambutol in growth and stasis may also apply to the benzothiazinethione class of drugs that inhibit DprE1, which helps make the acylated precursor for arabinogalactan and LAM synthesis.

    “this effectiveness activity profile in growth and stasis may also apply to the benzothiazinethione class of drugs that inhibit Dpre1, which helps make the acylated precursor for arabinogalactan and LaM synthesis150,151.”

    From The mycobacterial cell envelope — a moving target (2020) · cites this paper as [151]

    The Abstract identifies benzothiazinethiones as DprE1 inhibitors and says DprE1 helps produce a precursor for mycobacterial cell-wall arabinans. Results > Identification of benzothiazinethiones reports activity against replicating M. tuberculosis. The paper does not establish an ethambutol-like activity profile during stasis, or specifically describe an acylated precursor for both arabinogalactan and LAM synthesis. No page numbers are available in our copy. (LLM, conf=0.87)

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Research works printed but not linked: 44

  1. Poce G.. Sar analysis of new anti-tb drugs currently in pre-clinical and clinical development. Eur J Med Chem 86, 335– 351 (2014). 25173852
  2. Benoit L.. Tuberculosis drug discovery in the post-post-genomic era. EMBO Mol Med 6, 158– 168 (2014). 24401837 PMC3927952
  3. Zhao Y.. National survey of drug-resistant tuberculosis in China. N Engl J Med 366, 2161– 2170 (2012). 22670902
  4. Chaisson R. E. & Nuermberger E. L. Confronting multidrug-resistant tuberculosis. New N Engl J Med 366, 2223– 2224 (2012). 22670908
  5. Makoto M.. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med 3, e466 (2006). 17132069 PMC1664607
  6. Stover C. K.. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962– 966 (2000). 10879539
  7. Lienhardt C.. New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future. J Infect Dis 205, S241– 249 (2013). 22448022
  8. Bifani P.. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19, 1157– 1160 (2013). 23913123
  9. Ryan N. J. & Jin H. L. Delamanid: first global approval. Drugs 74, 1041– 1045 (2014). 24923253
  10. Yong-Soo K., Byeong-Ho J. & Won-Jung K. Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability. Expert Opin Pharmacother 16, 1– 9 (2015). 25327169
  11. Esposito S., Bianchini S. & Blasi F. Bedaquiline and delamanid in tuberculosis. Expert Opin Pharmacother 16, 2319– 2330 (2015). 26293803
  12. Barry C. E. Timing is everything for compassionate use of delamanid. Nat Med 21, 211 (2015). 25742452 PMC6380361
  13. Bloemberg G. V.. Acquired Resistance to Bedaquiline and Delamanid in Therapy for Tuberculosis. N Engl J Med 373, 1986– 1988 (2015). 26559594 PMC4681277
  14. Manina G.. Decaprenylphosphoryl-beta-d-ribose 2′-epimerase from mycobacterium tuberculosis is a magic drug target. Curr Med Chem 17, 3099– 108 (2010). 20629622
  15. Giovanna R.. The DprE1 enzyme, one of the most vulnerable targets of Mycobacterium tuberculosis. Appl Microbiol Biotechnol 97, 8841– 8848 (2013). 24037308
  16. Brecik M.. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem Biol 10, 1631– 1636 (2015). 25906160
  17. Makarov V.. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324, 801– 804 (2009). 19299584 PMC3128490
  18. Paul K.. Decaprenylphosphoryl-β-D-ribose 2′-epimerase, the target of benzothiazinones and dinitrobenzamides, is an essential enzyme in Mycobacterium smegmatis. Plos One 6, e16869 (2011). 21346818 PMC3035642
  19. Stanley S. A.. Identification of Novel Inhibitors of M. tuberculosis Growth Using Whole Cell Based High-Throughput Screening. ACS Chem Biol 7, 1377– 1384 (2012). 22577943 PMC3560293
  20. Ding S. Q. Identification of a small molecule with activity against drug-resistant and persistent tuberculosis. Proc Natl Acad Sci USA 110, 15848– 15849 (2013). PMC3703973 23776209
  21. Maruti N.. 4-aminoquinolone piperidine amides: noncovalent inhibitors of DprE1 with long residence time and potent antimycobacterial activity. J Med Chem 57, 5419– 5434 (2014). 24871036
  22. Manoranjan P.. Discovery of pyrazolopyridones as a novel class of noncovalent DprE1 inhibitor with potent anti-mycobacterial activity. J Med Chem 57, 4761– 4771 (2014). 24818517
  23. Shirude P. S.. Azaindoles: noncovalent DprE1 inhibitors from scaffold morphing efforts, kill Mycobacterium tuberculosis and are efficacious in vivo. J Med Chem 56, 9701– 9708 (2013). 24215368
  24. Makarov V.. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol Med 6, 372– 383 (2014). 24500695 PMC3958311
  25. Tomislav K.. Identification of antitubercular benzothiazinone compounds by ligand-based design. J Med Chem 55, 7940– 7944 (2012). 22916795
  26. Batt S. M.. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc Natl Acad Sci USA 109, 11354– 11359 (2012). 22733761 PMC3396498
  27. João N.. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Sci Transl Med 4, 1596– 1609 (2012). PMC3659392 22956199
  28. Gao C.. Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents. Bioorg Med Chem Lett 23, 4919– 4922 (2013). 23886691
  29. Peng C. T.. Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives. Bioorg Med Chem Lett 25, 1373– 1376 (2015). 25754492
  30. Kigondu E. M.. Pharmacologically active metabolites, combination screening and target identification-driven drug repositioning in antituberculosis drug discovery. Bioorg Med Chem 22, 4453– 4461 (2014). 24997576
  31. Salmaan K. & Farmer P. E. Tuberculosis, drug resistance, and the history of modern medicine. N Engl J Med 367, 931– 936 (2012). 22931261
  32. Benoit L., Hartkoorn R. C. & Cole S. T. In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob Agents Chemother 56, 5790– 5793 (2012). 22926573 PMC3486603
  33. Malwal S. R.. Design, Synthesis, and Evaluation of Thiol-Activated Sources of Sulfur Dioxide (SO2) as Antimycobacterial Agents. J Med Chem 55, 553– 557 (2012). 22128803
  34. Shi X.. 8-Hydroxy-2′-deoxyguanosine Formation and DNA Damage Induced by Sulfur Trioxide Anion Radicals. Biochem Biophys Res Commun 205, 141– 147 (1994). 7999014
  35. Armentia-Alvarez A.. Residual levels of free and total sulphite in fresh and cooked burgers. Food Addit Contam 10, 157– 65 (1993). 8314393
  36. Sirgel F. A.. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis. J Antimicrob Chemother 67, 1088– 1093 (2012). 22357804
  37. Jesús F.. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 56, 180– 185 (2005). 15911549
  38. Franzblau S. G.. Comprehensive analysis of methods used for the evaluation of compounds against Mycobacterium tuberculosis. Tuberculosis (Edinb) 92, 453– 488 (2012). 22940006
  39. Lun S.. Indoleamides are active against drug-resistant Mycobacterium tuberculosis.[J]. Nat Commun 4, 1294– 1296 (2013). PMC3909880 24352433
  40. Blaser A.. Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). J Med Chem 55, 312– 26 (2012). 22148391
  41. Collins L.. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob Agents Chemother 41, 1004– 1009 (1997). 9145860 PMC163841
  42. Wallace R. J. Jr.. Susceptibility Testing of Slowly Growing Mycobacteria by a Microdilution MIC Method with 7H9 Broth. J Clin Microbiol 24, 976– 981 (2005). 3097069 PMC269082
  43. Falzari K.. In vitro and in vivo activities of macrolide derivatives against mycobacterium tuberculosis. Antimicrob Agents Chemother 49, 1447– 1454 (2005). 15793125 PMC1068601
  44. Zhu Y.. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma. Sci Rep. 6, 20253 (2016). 26830149 PMC4735744

Cited by

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Authors
Gao, C., Peng, C., Shi, Y., You, X., Ran, K., Xiong, L., Ye, T.-H., Zhang, L., Wang, N., Zhu, Y., Liu, K., Zuo, W., Yu, L., & Wei, Y.
Affiliations
Sichuan University (CN)
Corresponding author
Yu, Luoting
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-07-13
Volume
6
Issue
1
Pages
29717-29717
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep29717
PMC
PMC4942819
OpenAlex
W2473900837
Cited by
48
References
3
Citations by year
2026: 3 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 5 · 2017: 2
FWCI
4.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Shanghai Pulmonary Hospital
  • National Science and Technology Major Project
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phenothiazines and Benzothiazines Synthesis and Activities
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Biological Evaluation
Keywords
drug-resistant tuberculosis, multidrug-resistant Mycobacterium tuberculosis, DprE1 inhibitors, antitubercular agents, extensively drug-resistant tuberculosis, mouse infection model
MeSH terms
Alcohol Oxidoreductases, Antitubercular Agents, Bacterial Proteins, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant

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