Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis

被引：633

作者：

Makarov, Vadim ^{[1
]}

Manina, Giulia ^{[2
]}

Mikusova, Katarina ^{[3
]}

Moellmann, Ute ^{[4
]}

Ryabova, Olga ^{[1
]}

Saint-Joanis, Brigitte ^{[5
]}

Dhar, Neeraj ^{[6
]}

Pasca, Maria Rosalia ^{[2
]}

Buroni, Silvia ^{[2
]}

Lucarelli, Anna Paola ^{[2
]}

Milano, Anna ^{[2
]}

De Rossi, Edda ^{[2
]}

Belanova, Martina ^{[3
]}

Bobovska, Adela ^{[3
]}

Dianiskova, Petronela ^{[3
]}

Kordulakova, Jana ^{[3
]}

Sala, Claudia ^{[6
]}

Fullam, Elizabeth ^{[6
]}

Schneider, Patricia ^{[6
]}

McKinney, John D. ^{[6
]}

Brodin, Priscille ^{[7
]}

Christophe, Thierry ^{[7
]}

Waddell, Simon ^{[8
]}

Butcher, Philip ^{[8
]}

Albrethsen, Jakob ^{[9
]}

Rosenkrands, Ida ^{[9
]}

Brosch, Roland ^{[5
]}

Nandi, Vrinda ^{[10
]}

Bharath, Sowmya ^{[10
]}

Gaonkar, Sheshagiri ^{[10
]}

Shandil, Radha K. ^{[10
]}

Balasubramanian, Venkataraman ^{[10
]}

Balganesh, Tanjore ^{[10
]}

Tyagi, Sandeep ^{[11
]}

Grosset, Jacques ^{[11
]}

Riccardi, Giovanna ^{[2
]}

Cole, Stewart T. ^{[6
]}

机构：

[1] Russian Acad Sci, AN Bakh Biochem Inst, Moscow 119071, Russia

[2] Univ Pavia, Dipartimento Genet & Microbiol, I-27100 Pavia, Italy

[3] Comenius Univ, Fac Nat Sci, Dept Biochem, Bratislava 84215, Slovakia

[4] Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, Dept Mol & Appl Microbiol, D-07745 Jena, Germany

[5] Inst Pasteur, F-75724 Paris 15, France

[6] Ecole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland

[7] Inst Pasteur Korea, Inserm Avenir Grp, Seoul 136791, South Korea

[8] Univ London St Georges Hosp, Div Cellular & Mol Med, London SE17 ORE, England

[9] Statens Serum Inst, Dept Infect Dis Immunol, DK-2300 Copenhagen S, Denmark

[10] AstraZeneca India, Bangalore, Karnataka, India

[11] Johns Hopkins Univ, Sch Med, Ctr TB Res, Baltimore, MD 21231 USA

来源：

SCIENCE | 2009年 / 324卷 / 5928期

基金：

英国惠康基金;

关键词：

CELL-WALL; IDENTIFICATION;

D O I：

10.1126/science.1171583

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：801 / 804

页数：4

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