Open Access
Science, volume 324, issue 5928, pages 801-804
Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
Makarov Vadim
1, 2
,
Manina Giulia
2, 3
,
Mikušová Katarína
2, 4
,
Möllmann Ute
2, 5
,
Ryabova Olga
1, 2
,
SAINT-JOANIS Brigitte
2, 6
,
Dhar Neeraj
7
,
Pasca Maria Rosalia
2, 3
,
Buroni Silvia
2, 3
,
Lucarelli Anna Paola
2, 3
,
Milano Anna
2, 3
,
De Rossi Edda
2, 3
,
Beláňová Martina
2, 4
,
Bobovská Adela
2, 4
,
Dianišková Petronela
2, 4
,
Korduláková Jana
2, 4
,
Sala Claudia
2, 7
,
Fullam Elizabeth
2, 7
,
Schneider Patricia
2, 7
,
McKinney John D.
7
,
Brodin Priscille
8
,
Christophe Thierry
8
,
Waddell Simon
2, 9
,
Butcher Philip
2, 9
,
ALBRETHSEN Jakob
2, 10
,
Rosenkrands Ida
2, 10
,
Brosch Roland
2, 6
,
Nandi Vrinda
2, 11
,
Bharath Sowmya
2, 11
,
Gaonkar Sheshagiri
2, 11
,
Shandil Radha. K.
2, 11
,
Balasubramanian Venkataraman
2, 11
,
Balganesh Tanjore
2, 11
,
Tyagi Sandeep
12
,
Grosset Jacques
12
,
Riccardi Giovanna
2, 3
,
Cole Stewart T
2, 7
2
New Medicines for Tuberculosis (NM4TB) Consortium ().
4
Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina, 84215 Bratislava, Slovakia.
|
5
Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology–Hans Knoell Institute, Beutenbergstrasse 11a, D-07745 Jena, Germany.
|
6
Institut Pasteur, Integrated Mycobacterial Pathogenomics, 25-28, Rue du Docteur Roux, 75724 Paris Cedex 15, France.
|
7
8
Inserm Avenir Group, Institut Pasteur Korea, 39-1 Hawolgok-dong, Seongbuk-gu, 136-791 Seoul, Korea.
|
9
Division of Cellular and Molecular Medicine, St. George’s Hospital, University of London, Cranmer Terrace, SW17 ORE London, UK.
|
11
AstraZeneca India, Bellary Road Hebbal, Bangalore, India.
|
Publication type: Journal Article
Publication date: 2009-05-08
PubMed ID:
19299584
Multidisciplinary
Abstract
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. An isomerase required for cell-wall synthesis is a target for an alternative drug lead for tuberculosis treatment. New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-β-d-ribose 2′-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.
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Makarov V. et al. Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis // Science. 2009. Vol. 324. No. 5928. pp. 801-804.
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Makarov V. et al. Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis // Science. 2009. Vol. 324. No. 5928. pp. 801-804.
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TY - JOUR
DO - 10.1126/science.1171583
UR - https://doi.org/10.1126%2Fscience.1171583
TI - Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
T2 - Science
AU - Makarov, Vadim
AU - Manina, Giulia
AU - Mikušová, Katarína
AU - Möllmann, Ute
AU - Ryabova, Olga
AU - SAINT-JOANIS, Brigitte
AU - Dhar, Neeraj
AU - Pasca, Maria Rosalia
AU - Buroni, Silvia
AU - Lucarelli, Anna Paola
AU - Milano, Anna
AU - De Rossi, Edda
AU - Beláňová, Martina
AU - Bobovská, Adela
AU - Dianišková, Petronela
AU - Korduláková, Jana
AU - Sala, Claudia
AU - Fullam, Elizabeth
AU - Schneider, Patricia
AU - McKinney, John D.
AU - Brodin, Priscille
AU - Christophe, Thierry
AU - Waddell, Simon
AU - Butcher, Philip
AU - ALBRETHSEN, Jakob
AU - Rosenkrands, Ida
AU - Brosch, Roland
AU - Nandi, Vrinda
AU - Bharath, Sowmya
AU - Gaonkar, Sheshagiri
AU - Shandil, Radha. K.
AU - Balasubramanian, Venkataraman
AU - Balganesh, Tanjore
AU - Tyagi, Sandeep
AU - Grosset, Jacques
AU - Riccardi, Giovanna
AU - Cole, Stewart T
PY - 2009
DA - 2009/05/08 00:00:00
PB - American Association for the Advancement of Science (AAAS)
SP - 801-804
IS - 5928
VL - 324
PMID - 19299584
SN - 0036-8075
SN - 1095-9203
ER -
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@article{2009_Makarov,
author = {Vadim Makarov and Giulia Manina and Katarína Mikušová and Ute Möllmann and Olga Ryabova and Brigitte SAINT-JOANIS and Neeraj Dhar and Maria Rosalia Pasca and Silvia Buroni and Anna Paola Lucarelli and Anna Milano and Edda De Rossi and Martina Beláňová and Adela Bobovská and Petronela Dianišková and Jana Korduláková and Claudia Sala and Elizabeth Fullam and Patricia Schneider and John D. McKinney and Priscille Brodin and Thierry Christophe and Simon Waddell and Philip Butcher and Jakob ALBRETHSEN and Ida Rosenkrands and Roland Brosch and Vrinda Nandi and Sowmya Bharath and Sheshagiri Gaonkar and Radha. K. Shandil and Venkataraman Balasubramanian and Tanjore Balganesh and Sandeep Tyagi and Jacques Grosset and Giovanna Riccardi and Stewart T Cole},
title = {Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis},
journal = {Science},
year = {2009},
volume = {324},
publisher = {American Association for the Advancement of Science (AAAS)},
month = {may},
url = {https://doi.org/10.1126%2Fscience.1171583},
number = {5928},
pages = {801--804},
doi = {10.1126/science.1171583}
}
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Makarov, Vadim, et al. “Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis.” Science, vol. 324, no. 5928, May. 2009, pp. 801-804. https://doi.org/10.1126%2Fscience.1171583.
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