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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry*
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Anti-Bacterial Agents / pharmacology*
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Anti-Bacterial Agents / therapeutic use
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / metabolism
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacology*
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Benzimidazoles / therapeutic use
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Cell Line
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Cell-Free System / metabolism
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DNA / metabolism
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Drug Discovery
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Inhibitory Concentration 50
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Mice
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Plague / drug therapy
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Structure-Activity Relationship
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism
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Virulence / drug effects
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Yersinia pestis / drug effects*
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Yersinia pestis / pathogenicity
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Yersinia pseudotuberculosis / drug effects*
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Yersinia pseudotuberculosis / pathogenicity
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Benzimidazoles
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Trans-Activators
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lcrF protein, Yersinia pestis
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DNA