Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Science. 2009 May 8;324(5928):801-4. doi: 10.1126/science.1171583. Epub 2009 Mar 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use*
  • Arabinose / metabolism
  • Cell Wall / metabolism
  • Drug Resistance, Bacterial
  • Enzyme Inhibitors / cerebrospinal fluid
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Ethambutol / pharmacology
  • Gene Expression Regulation, Bacterial / drug effects
  • Genes, Bacterial
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Molecular Sequence Data
  • Molecular Structure
  • Mycobacterium / drug effects
  • Mycobacterium / genetics
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism
  • Polysaccharides / biosynthesis*
  • Racemases and Epimerases / antagonists & inhibitors*
  • Racemases and Epimerases / metabolism
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Spiro Compounds / therapeutic use*
  • Thiazines / chemical synthesis
  • Thiazines / chemistry
  • Thiazines / pharmacology*
  • Thiazines / therapeutic use*
  • Tuberculosis / drug therapy*
  • Tuberculosis / microbiology

Substances

  • 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
  • Antitubercular Agents
  • Enzyme Inhibitors
  • Polysaccharides
  • Spiro Compounds
  • Thiazines
  • araban
  • Ethambutol
  • Arabinose
  • Racemases and Epimerases
  • decaprenylphosphoryl-beta-D-ribose 2'-epimerase, mouse