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Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis

2009; American Association for the Advancement of Science; Volume: 324; Issue: 5928 Linguagem: Inglês

10.1126/science.1171583

1095-9203

Vadim Makarov, Giulia Manina, Katarı́na Mikus̃ová, Ute Möllmann, O. B. Ryabova, Brigitte Saint‐Joanis, Neeraj Dhar, Maria Rosalia Pasca, Silvia Buroni, Anna Lucarelli, Anna Milano, Edda De Rossi, Martina Beláňová, Adela Bobovská, Petronela Dianišková, Jana Korduláková, Claudia Sala, Elizabeth Fullam, Patricia Schneider, John D. McKinney, Priscille Brodin, Thierry Christophe, Simon J. Waddell, Philip D. Butcher, Jakob Albrethsen, Ida Rosenkrands, Roland Brosch, Vrinda Nandi, Sowmya Bharath, Sheshagiri Gaonkar, Radha Krishan Shandil, V. Balasubramanian, Tanjore S. Balganesh, Sandeep Tyagi, J Grosset, Giovanna Riccardi, Stewart T. Cole,

Mycobacterium research and diagnosis

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.