title: N-hydroxybenzimidazole inhibitors of the transcription factor LcrF in Yersinia: novel antivirulence agents.
abstract: LcrF, a multiple adaptational response (MAR) transcription factor, regulates virulence in Yersinia pestis and Yersinia pseudotuberculosis. In a search for small molecule inhibitors of LcrF, an acrylic amide series of N-hydroxybenzimidazoles was synthesized and the SAR (structure-activity relationship) was examined. Selected test compounds demonstrated inhibitory activity in a primary cell-free LcrF-DNA binding assay as well as in a secondary whole cell assay (type III secretion system dependent Y. pseudotuberculosis cytotoxicity assay). The inhibitors exhibited no measurable antibacterial activity in vitro, confirming that they do not target bacterial growth. These results demonstrate that N-hydroxybenzimidazole inhibitors, exemplified by 14, 22, and 36, are effective antivirulence agents and have the potential to prevent infections caused by Yersinia spp.
authors.affiliation: Paratek Pharmaceuticals, Inc., 75 Kneeland Street, Boston, Massachusetts 02111, USA. okim@paratekpharm.com
authors.forename: Oak K
authors.initials: OK
authors.lastname: Kim
authors.forename: Lynne K
authors.initials: LK
authors.lastname: Garrity-Ryan
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Bartlett
authors.forename: Mark C
authors.initials: MC
authors.lastname: Grier
authors.forename: Atul K
authors.initials: AK
authors.lastname: Verma
authors.forename: Gabriel
authors.initials: G
authors.lastname: Medjanis
authors.forename: Janice E
authors.initials: JE
authors.lastname: Donatelli
authors.forename: Ann B
authors.initials: AB
authors.lastname: Macone
authors.forename: S Ken
authors.initials: SK
authors.lastname: Tanaka
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Levy
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alekshun
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D051379:Mice; D010930:Plague / Q000188:drug therapy; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014774:Virulence / Q000187:drug effects; D015010:Yersinia pestis / Q000187:drug effects* / Q000472:pathogenicity; D015011:Yersinia pseudotuberculosis / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D015534:Trans-Activators; C075515:lcrF protein, Yersinia pestis; D004247:DNA