araban and Tuberculosis

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.

Topics: Amino Acid Sequence; Animals; Antitubercular Agents; Arabinose; Cell Wall; Drug Resistance, Bacterial; Enzyme Inhibitors; Ethambutol; Gene Expression Regulation, Bacterial; Genes, Bacterial; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Sequence Data; Molecular Structure; Mycobacterium; Mycobacterium tuberculosis; Polysaccharides; Racemases and Epimerases; Spiro Compounds; Thiazines; Tuberculosis