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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

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  • Vadim Makarov
  • 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
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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.

Original languageEnglish
JournalScience
Volume324
Issue number5928
Pages (from-to)801-4
Number of pages4
DOIs
Publication statusPublished - 8 May 2009

    Research areas

  • Amino Acid Sequence, Animals, Antitubercular Agents, Arabinose, Cell Wall, Drug Resistance, Bacterial, Enzyme Inhibitors, Ethambutol, Gene Expression Regulation, Bacterial, Genes, Bacterial, Mice, Mice, Inbred BALB C, Microbial Sensitivity Tests, Molecular Sequence Data, Molecular Structure, Mycobacterium, Mycobacterium tuberculosis, Polysaccharides, Racemases and Epimerases, Spiro Compounds, Thiazines, Tuberculosis, Journal Article, Research Support, Non-U.S. Gov't

ID: 49496988