Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.
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.
Makarov
Vadim
V
A. N. Bakh Institute of Biochemistry, Russian Academy of Science, 119071 Moscow, Russia.
Manina
Giulia
G
Mikusova
Katarina
K
Möllmann
Ute
U
Ryabova
Olga
O
Saint-Joanis
Brigitte
B
Dhar
Neeraj
N
Pasca
Maria Rosalia
MR
Buroni
Silvia
S
Lucarelli
Anna Paola
AP
Milano
Anna
A
De Rossi
Edda
E
Belanova
Martina
M
Bobovska
Adela
A
Dianiskova
Petronela
P
Kordulakova
Jana
J
Sala
Claudia
C
Fullam
Elizabeth
E
Schneider
Patricia
P
McKinney
John D
JD
Brodin
Priscille
P
Christophe
Thierry
T
Waddell
Simon
S
Butcher
Philip
P
Albrethsen
Jakob
J
Rosenkrands
Ida
I
Brosch
Roland
R
Nandi
Vrinda
V
Bharath
Sowmya
S
Gaonkar
Sheshagiri
S
Shandil
Radha K
RK
Balasubramanian
Venkataraman
V
Balganesh
Tanjore
T
Tyagi
Sandeep
S
Grosset
Jacques
J
Riccardi
Giovanna
G
Cole
Stewart T
ST
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
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