N-Hydroxybenzimidazole Inhibitors of the Transcription Factor LcrF in Yersinia: Novel Antivirulence Agents
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- 作者：Oak K. Kim ; Lynne K. Garrity-Ryan ; Victoria J. Bartlett ; Mark C. Grier ; Atul K. Verma ; Gabriel Medjanis ; Janice E. Donatelli ; Ann B. Macone ; S. Ken Tanaka ; Stuart B. Levy ; Michael N. Alekshun
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：September 24, 2009
- 年：2009
- 卷：52
- 期：18
- 页码：5626-5634
- 全文大小：892K
- 年卷期：v.52,no.18(September 24, 2009)
- ISSN：1520-4804
文摘
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.