A new class of small molecule RNA polymerase inhibitors with activity against rifampicin-resistant Staphylococcus aureus.
The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
Arhin
Francis
F
Targanta Therapeutics Inc, 7170 Frederick Banting, 2nd Floor, St. Laurent, Que., Canada H4S 2A1.
Bélanger
Odette
O
Ciblat
Stéphane
S
Dehbi
Mohammed
M
Delorme
Daniel
D
Dietrich
Evelyne
E
Dixit
Dilip
D
Lafontaine
Yanick
Y
Lehoux
Dario
D
Liu
Jing
J
McKay
Geoffrey A
GA
Moeck
Greg
G
Reddy
Ranga
R
Rose
Yannick
Y
Srikumar
Ramakrishnan
R
Tanaka
Kelly S E
KS
Williams
Daniel M
DM
Gros
Philippe
P
Pelletier
Jerry
J
Parr
Thomas R
TR
Far
Adel Rafai
AR
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D015394:Molecular Structure; D008970:Molecular Weight; D012293:Rifampin / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
C514200:2-ureidothiophene-3-carboxylate; D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D013876:Thiophenes; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin