The loss of human lives to tuberculosis (TB) continues essentially unabated as a result of poverty, synergy with the HIV/ AIDS pandemic, and the emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. Despite some recent successes, such as the discovery of the diarylquinoline drug TMC207 and the promise of the bicyclic nitroimidazole compounds , and because of the high attrition rate in drug development , much greater effort is required to find better drugs in order to meet the desired goals of killing persistent tubercle bacilli and reducing TB treatment duration from 6 to less than 3 months.New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZ), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in murine models of TB. Using genetics and biochemistry, the enzyme decaprenylphosphoryl- -D-ribose 2’-epimerase was identified as a major BTZ target. Inhibition of this enzymatic activity abolishes formation of decaprenylphosphoryl arabinose, a key precursor 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.