Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
Open accessAbstract
Ammunition for the TB Wars: Tuberculosis is a major human disease of global importance resulting from infection with the air-borne pathogen Mycobacterium tuberculosis , which is becoming increasingly resistant to all available drugs. An antituberculosis benzothiazinone compound kills mycobacterium in infected cells and in mice. Makarov et al. (p. 801 ) have identified a sulfur atom and nitro residues important for benzothiazinone's activity and used genetic methods and biochemical analysis to identify its target in blocking arabinogalactan biosynthesis during cell-wall synthesis. The compound affects the same pathway as ethambutol, and thus a benzothiazinone drug has the potential to become an important part of treatment of drug-resistant disease and, possibly, replace the less effective ethambutol in the primary treatment of 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 [150]
In the paper’s main text (indexed under Abstract; page unavailable), BTZ043 is bactericidal against active M. tuberculosis but less effective in two models of metabolically inert bacteria. The paper also identifies DprE1 as a BTZ target and links its inhibition to loss of the precursor used to make arabinogalactan and lipoarabinomannan. It does not establish that ethambutol has the same growth-versus-stasis activity profile, and it calls the compounds benzothiazinones, not benzothiazinethiones; it describes the precursor as decaprenylphosphoryl arabinose, not an acylated precursor. (LLM, conf=0.86)
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The mycobacterial cell envelope — a moving target
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Cell Walls and Membranes of Actinobacteria
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- Authors
- Makarov, V., Manina, G., Mikusova, K., Möllmann, U., Ryabova, O., Saint-Joanis, B., Dhar, N., Pasca, M. R., Buroni, S., Lucarelli, A. P., Milano, A., De Rossi, E., Belanova, M., Bobovska, A., Dianiskova, P., Kordulakova, J., Sala, C., Fullam, E., Schneider, P., McKinney, J. D., Brodin, P., Christophe, T., Waddell, S., Butcher, P., Albrethsen, J., Rosenkrands, I., Brosch, R., Nandi, V., Bharath, S., Gaonkar, S., Shandil, R. K., Balasubramanian, V., Balganesh, T., Tyagi, S., Grosset, J., Riccardi, G., & Cole, S. T.
- Affiliations
- Russian Academy of Sciences (RU)
- University of Pavia (IT)
- New Medicines for Tuberculosis (NM4TB) Consortium ().
- Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- Institut Pasteur Korea (KR)
- University of London (GB)
- Statens Serum Institut (DK)
- Institut Pasteur (FR)
- AstraZeneca (India) (IN)
- Johns Hopkins University (US)
- Corresponding author
- Makarov, Vadim
- Manina, Giulia
- Möllmann, Ute
- Cole, Stewart T.
- ORCID
- Makarov, Vadim
- Manina, Giulia
- Dhar, Neeraj
- Pasca, Maria Rosalia
- Buroni, Silvia
- Sala, Claudia
- Fullam, Elizabeth
- McKinney, John D.
- Brodin, Priscille
- Waddell, Simon
- Butcher, Philip
- Albrethsen, Jakob
- Rosenkrands, Ida
- Brosch, Roland
- Shandil, Radha K.
- Balasubramanian, Venkataraman
- Tyagi, Sandeep
- Riccardi, Giovanna
- Cole, Stewart T.
- Venue
- Science
- Published
- 2009-05-08
- Volume
- 324
- Issue
- 5928
- Pages
- 801-804
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3128490
- OpenAlex
- W1976256007
- Cited by
- 740
- References
- 2
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 44 · 2023: 44 · 2022: 52 · 2021: 42 · 2020: 44 · 2019: 45 · 2018: 53 · 2017: 45 · 2016: 48 · 2015: 44 · 2014: 58 · 2013: 46 · 2012: 40
- FWCI
- 25.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust (062511, 080039)
- 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
- benzothiazinones, Mycobacterium tuberculosis, antimycobacterial agents, cell wall biosynthesis, drug-resistant tuberculosis, combination therapy
- MeSH terms
- Amino Acid Sequence, Animals, Antitubercular Agents, Arabinose, Cell Wall, Enzyme Inhibitors, Ethambutol, Genes, Bacterial, Mice, Inbred BALB C, Microbial Sensitivity Tests, Molecular Sequence Data, Mycobacterium, Mycobacterium tuberculosis, Polysaccharides, Spiro Compounds, Thiazines, Tuberculosis, Molecular Structure, Gene Expression Regulation, Bacterial, Racemases and Epimerases, Drug Resistance, Bacterial, Mice
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