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
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antitubercular Agents / chemical synthesis
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Antitubercular Agents / therapeutic use*
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Arabinose / metabolism
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Cell Wall / metabolism
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Drug Resistance, Bacterial
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Enzyme Inhibitors / cerebrospinal fluid
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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Ethambutol / pharmacology
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Gene Expression Regulation, Bacterial / drug effects
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Genes, Bacterial
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Mice
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Mice, Inbred BALB C
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Microbial Sensitivity Tests
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Molecular Sequence Data
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Molecular Structure
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Mycobacterium / drug effects
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Mycobacterium / genetics
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / metabolism
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Polysaccharides / biosynthesis*
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Racemases and Epimerases / antagonists & inhibitors*
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Racemases and Epimerases / metabolism
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology*
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Spiro Compounds / therapeutic use*
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Thiazines / chemical synthesis
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Thiazines / chemistry
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Thiazines / pharmacology*
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Thiazines / therapeutic use*
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Tuberculosis / drug therapy*
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Tuberculosis / microbiology
Substances
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2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one
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Antitubercular Agents
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Enzyme Inhibitors
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Polysaccharides
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Spiro Compounds
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Thiazines
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araban
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Ethambutol
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Arabinose
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Racemases and Epimerases
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decaprenylphosphoryl-beta-D-ribose 2'-epimerase, mouse