Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis
- Makarov, Vadim
- Manina, Giulia
- Mikusova, Katarina
- Möllmann, Ute
- Ryabova, Olga
- Saint-Joanis, Brigitte
- Dhar, Neeraj
- Pasca, Maria Rosalia
- Buroni, Silvia
- Lucarelli, Anna Paola
- Milano, Anna
- De Rossi, Edda
- Belanova, Martina
- Bobovska, Adela
- Dianiskova, Petronela
- Kordulakova, Jana
- Sala, Claudia
- Fullam, Elizabeth
- Schneider, Patricia
- McKinney, John D
- Brodin, Priscille
- Christophe, Thierry
- Waddell, Simon
- Butcher, Philip
- Albrethsen, Jakob
- Rosenkrands, Ida
- Brosch, Roland
- Nandi, Vrinda
- Bharath, Sowmya
- Gaonkar, Sheshagiri
- Shandil, Radha K
- Balasubramanian, Venkataraman
- Balganesh, Tanjore
- Tyagi, Sandeep
- Grosset, Jacques
- Riccardi, Giovanna
- Cole, Stewart T
DOIAbstract
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 ext...
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