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Статья
Benzothiazinones Kill Mycobacterium tuberculosis by blocking Arabinan synthesis
2021
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-β-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.
Цитирование
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Версии
- 1. Version of Record от 2021-04-27
Метаданные
Название журнала
- Science
Том
- 324
Выпуск
- 5928
Страницы
- 801-804
Ключевые слова
- 1,3 benzothiazinon 4 one; 2 [2 methyl 1,4 dioxa 8 azaspiro[4.5]dec 8 yl] 8 nitro 6 (trifluoromethyl) 4h 1,3 benzothiazin 4 one; arabinan; arabinose; bacterial enzyme; btz 038; btz 043; btz 044; decaprenylphosphoryl arabinose; decaprenylphosphoryl beta dextro ribose 2' epimerase; ethambutol; green fluorescent protein; isoniazid; tuberculostatic agent; unclassified drug; 2 (2 methyl 1,4 dioxa 8 azaspiro(4.5)dec 8 yl) 8 nitro 6 (trifluoromethyl) 4H 1,3 benzothiazin 4 one; 2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; araban; decaprenylphosphoryl beta D ribose 2' epimerase, mouse; decaprenylphosphoryl-beta-D-ribose 2'-epimerase, mouse; enzyme inhibitor; ethambutol; isomerase; polysaccharide; spiro compound; thiazine derivative; tuberculostatic agent; bacterium; biochemistry; cell organelle; drug; genetic analysis; lysis; tuberculosis; animal experiment; animal model; antibacterial activity; article; bactericidal activity; chronic disease; controlled study; drug efficacy; drug potency; drug screening; drug structure; drug synthesis; drug targeting; enzyme inhibition; fluorescence microscopy; minimum inhibitory concentration; mouse; multidrug resistance; Mycobacterium; Mycobacterium tuberculosis; nonhuman; priority journal; structure activity relation; toxicity testing; treatment outcome; tuberculosis; amino acid sequence; animal; antibiotic resistance; bacterial gene; Bagg albino mouse; biosynthesis; cell wall; cerebrospinal fluid; chemical structure; chemistry; drug antagonism; drug effect; gene expression regulation; genetics; metabolism; microbiological examination; microbiology; molecular genetics; synthesis; tuberculosis; Bacteria (microorganisms); Mycobacterium tuberculosis; 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
Тип документа
- journal article
Источник
- scopus
