Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis

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. McKinneyPriscille 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

Research output: Contribution to journalArticlepeer-review

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-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.

Original languageEnglish (US)
Pages (from-to)801-804
Number of pages4
JournalScience
Volume324
Issue number5928
DOIs
StatePublished - May 8 2009

ASJC Scopus subject areas

  • General

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