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

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698 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Science
Vol/bind	324
Udgave nummer	5928
Sider (fra-til)	801-4
Antal sider	4
DOI	https://doi.org/10.1126/science.1171583
Status	Udgivet - 8 maj 2009

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10.1126/science.1171583

Citationsformater

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, bind 324, nr. 5928, s. 801-4. https://doi.org/10.1126/science.1171583

@article{de36bcd9e5f84f0aa57a8da68ad43abb,

title = "Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis",

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.",

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",

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

year = "2009",

month = may,

day = "8",

doi = "10.1126/science.1171583",

language = "English",

volume = "324",

pages = "801--4",

journal = "Science",

issn = "1095-9203",

publisher = "American Association for the Advancement of Science",

number = "5928",

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TY - JOUR

T1 - Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

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

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