title: A new class of small molecule RNA polymerase inhibitors with activity against rifampicin-resistant Staphylococcus aureus.
abstract: 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.
authors.affiliation: Targanta Therapeutics Inc, 7170 Frederick Banting, 2nd Floor, St. Laurent, Que., Canada H4S 2A1.
authors.forename: Francis
authors.initials: F
authors.lastname: Arhin
authors.forename: Odette
authors.initials: O
authors.lastname: Bélanger
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ciblat
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dehbi
authors.forename: Daniel
authors.initials: D
authors.lastname: Delorme
authors.forename: Evelyne
authors.initials: E
authors.lastname: Dietrich
authors.forename: Dilip
authors.initials: D
authors.lastname: Dixit
authors.forename: Yanick
authors.initials: Y
authors.lastname: Lafontaine
authors.forename: Dario
authors.initials: D
authors.lastname: Lehoux
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: McKay
authors.forename: Greg
authors.initials: G
authors.lastname: Moeck
authors.forename: Ranga
authors.initials: R
authors.lastname: Reddy
authors.forename: Yannick
authors.initials: Y
authors.lastname: Rose
authors.forename: Ramakrishnan
authors.initials: R
authors.lastname: Srikumar
authors.forename: Kelly S E
authors.initials: KS
authors.lastname: Tanaka
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Williams
authors.forename: Philippe
authors.initials: P
authors.lastname: Gros
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Parr
authors.forename: Adel Rafai
authors.initials: AR
authors.lastname: Far
mesh_terms: 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*
chemical_list: C514200:2-ureidothiophene-3-carboxylate; D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D013876:Thiophenes; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin