Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis | Zendy

Vadim Makarov | Zendy; Giulia Manina | Zendy; Katarı́na Mikus̃ová | Zendy; Ute Möllmann | Zendy; O. B. Ryabova | Zendy; Brigitte SaintJoanis | Zendy; Neeraj Dhar | Zendy; Maria Rosalia Pasca | Zendy; Silvia Buroni | Zendy; Anna Lucarelli | Zendy; Anna Milano | Zendy; Edda De Rossi | Zendy; Martina Beláňová | Zendy; Adela Bobovská | Zendy; Petronela Dianišková | Zendy; Jana Korduláková | Zendy; Claudia Sala | Zendy; Elizabeth Fullam | Zendy; Patricia Schneider | Zendy; John D. McKinney | Zendy; Priscille Brodin | Zendy; Thierry Christophe | Zendy; Simon J. Waddell | Zendy; Philip D. Butcher | Zendy; Jakob Albrethsen | Zendy; Ida Rosenkrands | Zendy; Roland Brosch | Zendy; Vrinda Nandi | Zendy; Sowmya Bharath | Zendy; Sheshagiri Gaonkar | Zendy; Radha Krishan Shandil | Zendy; V. Balasubramanian | Zendy; Tanjore S. Balganesh | Zendy; Sandeep Tyagi | Zendy; J Grosset | Zendy; Giovanna Riccardi | Zendy; Stewart T. Cole | Zendy

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Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis

Author(s) -

Vadim Makarov,

Giulia Manina,

Katarı́na Mikus̃ová,

Ute Möllmann,

O. B. Ryabova,

Brigitte SaintJoanis,

Neeraj Dhar,

Maria Rosalia Pasca,

Silvia Buroni,

Anna Lucarelli,

Anna Milano,

Edda De Rossi,

Martina Beláňová,

Adela Bobovská,

Petronela Dianišková,

Jana Korduláková,

Claudia Sala,

Elizabeth Fullam,

Patricia Schneider,

John D. McKinney,

Priscille Brodin,

Thierry Christophe,

Simon J. Waddell,

Philip D. Butcher,

Jakob Albrethsen,

Ida Rosenkrands,

Roland Brosch,

Vrinda Nandi,

Sowmya Bharath,

Sheshagiri Gaonkar,

Radha Krishan Shandil,

V. Balasubramanian,

Tanjore S. Balganesh,

Sandeep Tyagi,

J Grosset,

Giovanna Riccardi,

Stewart T. Cole

Publication year - 2009

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.1171583

Subject(s) - ethambutol , mycobacterium tuberculosis , tuberculosis , microbiology and biotechnology , lipoarabinomannan , arabinogalactan , drug , pathogen , mycobacterium , biology , medicine , virology , pharmacology , cell wall , biochemistry , pathology

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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