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

Department of Growth and Reproduction

653 Citations (Scopus)

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-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.

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

Keywords

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
Journal Article
Research Support, Non-U.S. Gov't

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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), 801-4. 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. 801-4. 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-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.",

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AU - Makarov, Vadim

AU - Manina, Giulia

AU - Mikusova, Katarina

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

PY - 2009/5/8

Y1 - 2009/5/8

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Antitubercular Agents

KW - Arabinose

KW - Cell Wall

KW - Drug Resistance, Bacterial

KW - Enzyme Inhibitors

KW - Ethambutol

KW - Gene Expression Regulation, Bacterial

KW - Genes, Bacterial

KW - Mice

KW - Mice, Inbred BALB C

KW - Microbial Sensitivity Tests

KW - Molecular Sequence Data

KW - Molecular Structure

KW - Mycobacterium

KW - Mycobacterium tuberculosis

KW - Polysaccharides

KW - Racemases and Epimerases

KW - Spiro Compounds

KW - Thiazines

KW - Tuberculosis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1126/science.1171583

DO - 10.1126/science.1171583

M3 - Journal article

C2 - 19299584

SN - 1095-9203

VL - 324

SP - 801

EP - 804

JO - Science

JF - Science

IS - 5928

ER -

Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Abstract

Keywords

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