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.
authors.affiliation: A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.
authors.forename: Vadim
authors.initials: V
authors.lastname: Makarov
authors.forename: Giulia
authors.initials: G
authors.lastname: Manina
authors.forename: Katarina
authors.initials: K
authors.lastname: Mikusova
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
authors.forename: Olga
authors.initials: O
authors.lastname: Ryabova
authors.forename: Brigitte
authors.initials: B
authors.lastname: Saint-Joanis
authors.forename: Neeraj
authors.initials: N
authors.lastname: Dhar
authors.forename: Maria Rosalia
authors.initials: MR
authors.lastname: Pasca
authors.forename: Silvia
authors.initials: S
authors.lastname: Buroni
authors.forename: Anna Paola
authors.initials: AP
authors.lastname: Lucarelli
authors.forename: Anna
authors.initials: A
authors.lastname: Milano
authors.forename: Edda
authors.initials: E
authors.lastname: De Rossi
authors.forename: Martina
authors.initials: M
authors.lastname: Belanova
authors.forename: Adela
authors.initials: A
authors.lastname: Bobovska
authors.forename: Petronela
authors.initials: P
authors.lastname: Dianiskova
authors.forename: Jana
authors.initials: J
authors.lastname: Kordulakova
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fullam
authors.forename: Patricia
authors.initials: P
authors.lastname: Schneider
authors.forename: John D
authors.initials: JD
authors.lastname: McKinney
authors.forename: Priscille
authors.initials: P
authors.lastname: Brodin
authors.forename: Thierry
authors.initials: T
authors.lastname: Christophe
authors.forename: Simon
authors.initials: S
authors.lastname: Waddell
authors.forename: Philip
authors.initials: P
authors.lastname: Butcher
authors.forename: Jakob
authors.initials: J
authors.lastname: Albrethsen
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Vrinda
authors.initials: V
authors.lastname: Nandi
authors.forename: Sowmya
authors.initials: S
authors.lastname: Bharath
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.forename: Radha K
authors.initials: RK
authors.lastname: Shandil
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Balasubramanian
authors.forename: Tanjore
authors.initials: T
authors.lastname: Balganesh
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.forename: Jacques
authors.initials: J
authors.lastname: Grosset
authors.forename: Giovanna
authors.initials: G
authors.lastname: Riccardi
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001089:Arabinose / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004977:Ethambutol / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009161:Mycobacterium / Q000187:drug effects / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000096:biosynthesis*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011134:Polysaccharides; D013141:Spiro Compounds; D013843:Thiazines; C030080:araban; D004977:Ethambutol; D001089:Arabinose; D019998:Racemases and Epimerases; C540717:decaprenylphosphoryl-beta-D-ribose 2'-epimerase, mouse