Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis.
Benzothiazinones (BTZs) form a new class of potent antimycobacterial agents. Although the target of BTZs has been identified as decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), their detailed mechanism of action remains obscure. Here we demonstrate that BTZs are activated in the bacterium by reduction of an essential nitro group to a nitroso derivative, which then specifically reacts with a cysteine residue in the active site of DprE1.
Trefzer
Claudia
C
New Medicines for Tuberculosis Consortium, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Rengifo-Gonzalez
Monica
M
Hinner
Marlon J
MJ
Schneider
Patricia
P
Makarov
Vadim
V
Cole
Stewart T
ST
Johnsson
Kai
K
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D011355:Prodrugs; D013843:Thiazines; D019998:Racemases and Epimerases