Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis

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

doi:10.1126/science.1171583

Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

502 Scopus citations

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-β-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.

Original language	English (US)
Pages (from-to)	801-804
Number of pages	4
Journal	Science
Volume	324
Issue number	5928
DOIs	https://doi.org/10.1126/science.1171583
State	Published - May 8 2009

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Makarov, V., Manina, G., Mikusova, K., Möllmann, U., Ryabova, O., Saint-Joanis, B., Dhar, N., Pasca, M. R., Buroni, S., Lucarelli, A. P., Milano, A., De Rossi, E., Belanova, M., Bobovska, A., Dianiskova, P., Kordulakova, J., Sala, C., Fullam, E., Schneider, P., ... Cole, S. T. (2009). Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis. Science, 324(5928), 801-804. https://doi.org/10.1126/science.1171583

Makarov, V, Manina, G, Mikusova, K, Möllmann, U, Ryabova, O, Saint-Joanis, B, Dhar, N, Pasca, MR, Buroni, S, Lucarelli, AP, Milano, A, De Rossi, E, Belanova, M, Bobovska, A, Dianiskova, P, Kordulakova, J, Sala, C, Fullam, E, Schneider, P, McKinney, JD, Brodin, P, Christophe, T, Waddell, S, Butcher, P, Albrethsen, J, Rosenkrands, I, Brosch, R, Nandi, V, Bharath, S, Gaonkar, S, Shandil, RK, Balasubramanian, V, Balganesh, T, Tyagi, S, Grosset, J, Riccardi, G & Cole, ST 2009, 'Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis', Science, vol. 324, no. 5928, pp. 801-804. https://doi.org/10.1126/science.1171583

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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-β-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.",

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AU - Manina, Giulia

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AU - Möllmann, Ute

AU - Ryabova, Olga

AU - Saint-Joanis, Brigitte

AU - Dhar, Neeraj

AU - Pasca, Maria Rosalia

AU - Buroni, Silvia

AU - Lucarelli, Anna Paola

AU - Milano, Anna

AU - De Rossi, Edda

AU - Belanova, Martina

AU - Bobovska, Adela

AU - Dianiskova, Petronela

AU - Kordulakova, Jana

AU - Sala, Claudia

AU - Fullam, Elizabeth

AU - Schneider, Patricia

AU - McKinney, John D.

AU - Brodin, Priscille

AU - Christophe, Thierry

AU - Waddell, Simon

AU - Butcher, Philip

AU - Albrethsen, Jakob

AU - Rosenkrands, Ida

AU - Brosch, Roland

AU - Nandi, Vrinda

AU - Bharath, Sowmya

AU - Gaonkar, Sheshagiri

AU - Shandil, Radha K.

AU - Balasubramanian, Venkataraman

AU - Balganesh, Tanjore

AU - Tyagi, Sandeep

AU - Grosset, Jacques

AU - Riccardi, Giovanna

AU - Cole, Stewart T.

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Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis

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