Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis.

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Bibliographic Details
Title:	Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis.
Authors:	Makarov, Vadim, Manina, Giulia, Mikusova, Katarina, Möllmann, Ute, Ryabova, Olga, Saint-Joanis, Brigitte, Dhar, Neeraj, Pasca, Maria Rosalia, Buroni, Silvia, Lucarelli, Anna Paola, Milano, Anna, De Rossi, Edda, Belanova, Martina, Bobovska, Adela, Dianiskova, Petronela, Kordulakova, Jana, Sala, Claudia, Fullam, Elizabeth, Schneider, Patricia, McKinney, John D.
Source:	Science (pre-March 2025). 5/8/2009, Vol. 324 Issue 5928, p801-804. 4p.
Subjects:	Benzothiazine, Mycobacterium tuberculosis, Pandemics, Antibacterial agents, Laboratory mice, Genetic research, Biochemical research, Therapeutics
Abstract:	New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazln-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. [ABSTRACT FROM AUTHOR]
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Database:	Psychology and Behavioral Sciences Collection

Description
Abstract:	New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazln-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. [ABSTRACT FROM AUTHOR]
ISSN:	00368075
DOI:	10.1126/science.1171583