Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis

Makarov, Vadim, Manina, Giulia, Mikusova, Katarina, Möllmann, Ute, Ryabova, Olga, Saint-Joanis, Brigitte, Dhar, Neeraj, Pasca, Maria Rosalia, Buroni, Silvia, Lucarelli, Anna Paola, Milano, Anna, De Rossi, Edda, Belanova, Martina, Bobovska, Adela, Dianiskova, Petronela, Kordulakova, Jana, Sala, Claudia, Fullam, Elizabeth, Schneider, Patricia, McKinney, John D, Brodin, Priscille, Christophe, Thierry, Waddell, Simon, Butcher, Philip, Albrethsen, Jakob, Rosenkrands, Ida, Brosch, Roland, Nandi, Vrinda, Bharath, Sowmya, Gaonkar, Sheshagiri, Shandil, Radha K, Balasubramanian, Venkataraman, Balganesh, Tanjore, Tyagi, Sandeep, Grosset, Jacques, Riccardi, Giovanna and Cole, Stewart T (2009) Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 324 (5928). pp. 801-804. ISSN 0036-8075

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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.

Item Type: Article
Additional Information: CODEN: SCIEA PubMed ID: 19299584
Keywords: Mycobacterium Tuberculosis Drug discovery Transcriptional profiling Infection
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: Q Science > QR Microbiology > QR0075 Bacteria
R Medicine > R Medicine (General)
Depositing User: Simon Waddell
Date Deposited: 22 Aug 2011 13:29
Last Modified: 07 Mar 2017 06:43
URI: http://sro.sussex.ac.uk/id/eprint/7062
Google Scholar:66 Citations

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