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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis
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(2009) Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science (New York, N.Y.), Volume 324 (Number 5928). pp. 801-804. doi:10.1126/science.1171583 ISSN 1095-9203.
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Official URL: http://dx.doi.org/10.1126/science.1171583
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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Science (New York, N.Y.) | ||||
Publisher: | American Association for the Advancement of Science | ||||
ISSN: | 1095-9203 | ||||
Official Date: | 8 May 2009 | ||||
Dates: |
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Volume: | Volume 324 | ||||
Number: | Number 5928 | ||||
Page Range: | pp. 801-804 | ||||
DOI: | 10.1126/science.1171583 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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