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Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis
journal contribution
posted on 2023-06-07, 15:59 authored by 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 WaddellSimon 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 ColeNew 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.
History
Publication status
- Published
File Version
- Accepted version
Journal
ScienceISSN
0036-8075Publisher
American Association for the Advancement of ScienceExternal DOI
Issue
5928Volume
324Page range
801-804Department affiliated with
- Clinical and Experimental Medicine Publications
Notes
CODEN: SCIEA PubMed ID: 19299584Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2011-08-22First Open Access (FOA) Date
2017-01-10First Compliant Deposit (FCD) Date
2017-01-10Usage metrics
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