Submitted on January 29, 2009
Accepted on March 13, 2009

Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis

Vadim Makarov ¹, Giulia Manina ², Katarina Mikusova ³, Ute Möllmann ⁴, Olga Ryabova ⁵, Brigitte Saint-Joanis ⁶, Neeraj Dhar ⁷, Maria Rosalia Pasca ², Silvia Buroni ², Anna Paola Lucarelli ², Anna Milano ², Edda De Rossi ², Martina Belanova ³, Adela Bobovska ³, Petronela Dianiskova ³, Jana Kordulakova ³, Claudia Sala ⁸, Elizabeth Fullam ⁸, Patricia Schneider ⁸, John D. McKinney ⁷, Priscille Brodin ⁹, Thierry Christophe ⁹, Simon Waddell ¹⁰, Philip Butcher ¹⁰, Jakob Albrethsen ¹¹, Ida Rosenkrands ¹¹, Roland Brosch ⁶, Vrinda Nandi ¹², Sowmya Bharath ¹², Sheshagiri Gaonkar ¹², Radha K Shandil ¹², V. Balasubramanian ¹², Tanjore Balganesh ¹², Sandeep Tyagi ¹², Jacques Grosset ¹³, Giovanna Riccardi ², Stewart T. Cole ^6*

¹ New Medicines for Tuberculosis Consortium.; A.N. Bakh Institute of Biochemistry, RAS, Moscow 119071, Russia.
² New Medicines for Tuberculosis Consortium.; Dipartimento di Genetica e Microbiologia, Università degli Studi di Pavia, via Ferrata, 1, 27100 Pavia, Italy.
³ New Medicines for Tuberculosis Consortium.; Department of Biochemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina, 84215 Bratislava, Slovakia.
⁴ New Medicines for Tuberculosis Consortium.; Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Beutenbergstr. 11a, D-07745 Jena, Germany.
⁵ A.N. Bakh Institute of Biochemistry, RAS, Moscow 119071, Russia.
⁶ New Medicines for Tuberculosis Consortium.; Institut Pasteur, Integrated Mycobacterial Pathogenomics, 25-28, rue du Docteur Roux, 75724 Paris Cedex 15, France.
⁷ Global Health Institute, EPFL, CH-1015 Lausanne, Switzerland
⁸ New Medicines for Tuberculosis Consortium.; Global Health Institute, EPFL, CH-1015 Lausanne, Switzerland
⁹ Inserm Avenir Group, Institut Pasteur Korea, 39-1 Hawolgok-dong, Seongbuk-gu, Seoul, 136-791, Korea.
¹⁰ New Medicines for Tuberculosis Consortium.; Division of Cellular and Molecular Medicine, St. George's, University of London, Cranmer Terrace, London SW17 ORE, United Kingdom.
¹¹ New Medicines for Tuberculosis Consortium.; Statens Serum Institut, Department of Infectious Disease Immunology, Artillerivej 5, DK-2300 Copenhagen S, Denmark.
¹² New Medicines for Tuberculosis Consortium.; AstraZeneca India, Bellary Road Hebbal, Bangalore, India.
¹³ Center for TB Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

^* To whom correspondence should be addressed.
Stewart T. Cole , E-mail: stewart.cole{at}epfl.ch

These authors contributed equally to this work.

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZ), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in murine models of TB. Using genetics and biochemistry, the enzyme decaprenylphosphoryl--D-ribose 2’-epimerase was identified as a major BTZ target. Inhibition of this enzymatic activity abolishes formation of decaprenylphosphoryl arabinose, a key precursor 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.