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Originally published in Science Express on 19 March 2009
Science 8 May 2009:
Vol. 324. no. 5928, pp. 801 - 804
DOI: 10.1126/science.1171583
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Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis

Vadim Makarov,1,2,* Giulia Manina,1,3,* Katarina Mikusova,1,4,* Ute Möllmann,1,5,* Olga Ryabova,1,2 Brigitte Saint-Joanis,1,6 Neeraj Dhar,7 Maria Rosalia Pasca,1,3 Silvia Buroni,1,3 Anna Paola Lucarelli,1,3 Anna Milano,1,3 Edda De Rossi,1,3 Martina Belanova,1,4 Adela Bobovska,1,4 Petronela Dianiskova,1,4 Jana Kordulakova,1,4 Claudia Sala,1,7 Elizabeth Fullam,1,7 Patricia Schneider,1,7 John D. McKinney,7 Priscille Brodin,8 Thierry Christophe,8 Simon Waddell,1,9 Philip Butcher,1,9 Jakob Albrethsen,1,10 Ida Rosenkrands,1,10 Roland Brosch,1,6 Vrinda Nandi,1,11 Sowmya Bharath,1,11 Sheshagiri Gaonkar,1,11 Radha K. Shandil,1,11 Venkataraman Balasubramanian,1,11 Tanjore Balganesh,1,11 Sandeep Tyagi,12 Jacques Grosset,12 Giovanna Riccardi,1,3 Stewart T. Cole1,7,{dagger}

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.

1 New Medicines for Tuberculosis (NM4TB) Consortium (www.nm4tb.org).
2 A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.
3 Dipartimento di Genetica e Microbiologia, Università degli Studi di Pavia, via Ferrata, 1, 27100 Pavia, Italy.
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 Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
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.
10 Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, DK-2300 Copenhagen S, Denmark.
11 AstraZeneca India, Bellary Road Hebbal, Bangalore, India.
12 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: stewart.cole{at}epfl.ch

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