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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.


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.

SUBMITTER: Makarov V 

PROVIDER: S-EPMC3128490 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

Makarov Vadim V   Manina Giulia G   Mikusova Katarina K   Möllmann Ute U   Ryabova Olga O   Saint-Joanis Brigitte B   Dhar Neeraj N   Pasca Maria Rosalia MR   Buroni Silvia S   Lucarelli Anna Paola AP   Milano Anna A   De Rossi Edda E   Belanova Martina M   Bobovska Adela A   Dianiskova Petronela P   Kordulakova Jana J   Sala Claudia C   Fullam Elizabeth E   Schneider Patricia P   McKinney John D JD   Brodin Priscille P   Christophe Thierry T   Waddell Simon S   Butcher Philip P   Albrethsen Jakob J   Rosenkrands Ida I   Brosch Roland R   Nandi Vrinda V   Bharath Sowmya S   Gaonkar Sheshagiri S   Shandil Radha K RK   Balasubramanian Venkataraman V   Balganesh Tanjore T   Tyagi Sandeep S   Grosset Jacques J   Riccardi Giovanna G   Cole Stewart T ST  

Science (New York, N.Y.) 20090319 5928


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 arabinos  ...[more]

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