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-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.
- Publication:
-
Science
- Pub Date:
- May 2009
- DOI:
- 10.1126/science.1171583
- Bibcode:
- 2009Sci...324..801M
- Keywords:
-
- MICROBIO