N-hydroxybenzimidazole inhibitors of the transcription factor LcrF in Yersinia: novel antivirulence agents.
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.
Kim
Oak K
OK
Paratek Pharmaceuticals, Inc., 75 Kneeland Street, Boston, Massachusetts 02111, USA. okim@paratekpharm.com
Garrity-Ryan
Lynne K
LK
Bartlett
Victoria J
VJ
Grier
Mark C
MC
Verma
Atul K
AK
Medjanis
Gabriel
G
Donatelli
Janice E
JE
Macone
Ann B
AB
Tanaka
S Ken
SK
Levy
Stuart B
SB
Alekshun
Michael N
MN
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
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D015534:Trans-Activators; C075515:lcrF protein, Yersinia pestis; D004247:DNA