2. Academic Validation
  3. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

  • Science. 2009 May 8;324(5928):801-4. doi: 10.1126/science.1171583.
Vadim Makarov 1,  Giulia Manina,  Katarina Mikusova,  Ute Möllmann,  Olga Ryabova,  Brigitte Saint-Joanis,  Neeraj Dhar,  Maria Rosalia Pasca,  Silvia Buroni,  Anna Paola Lucarelli,  Anna Milano,  Edda De Rossi,  Martina Belanova,  Adela Bobovska,  Petronela Dianiskova,  Jana Kordulakova,  Claudia Sala,  Elizabeth Fullam,  Patricia Schneider,  John D McKinney,  Priscille Brodin,  Thierry Christophe,  Simon Waddell,  Philip Butcher,  Jakob Albrethsen,  Ida Rosenkrands,  Roland Brosch,  Vrinda Nandi,  Sowmya Bharath,  Sheshagiri Gaonkar,  Radha K Shandil,  Venkataraman Balasubramanian,  Tanjore Balganesh,  Sandeep Tyagi,  Jacques Grosset,  Giovanna Riccardi,  Stewart T Cole
Affiliations

Affiliation

  • 1 A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.
PMID: 19299584 DOI: 10.1126/science.1171583
Abstract

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-beta-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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