Document Detail


Small molecule inhibitors of LcrF, a Yersinia pseudotuberculosis transcription factor, attenuate virulence and limit infection in a murine pneumonia model.
MedLine Citation:
PMID:  20823209     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
LcrF (VirF), a transcription factor in the multiple adaptational response (MAR) family, regulates expression of the Yersinia type III secretion system (T3SS). Yersinia pseudotuberculosis lcrF-null mutants showed attenuated virulence in tissue culture and animal models of infection. Targeting of LcrF offers a novel, antivirulence strategy for preventing Yersinia infection. A small molecule library was screened for inhibition of LcrF-DNA binding in an in vitro assay. All of the compounds lacked intrinsic antibacterial activity and did not demonstrate toxicity against mammalian cells. A subset of these compounds inhibited T3SS-dependent cytotoxicity of Y. pseudotuberculosis toward macrophages in vitro. In a murine model of Y. pseudotuberculosis pneumonia, two compounds significantly reduced the bacterial burden in the lungs and afforded a dramatic survival advantage. The MAR family of transcription factors is well conserved, with members playing central roles in pathogenesis across bacterial genera; thus, the inhibitors could have broad applicability.
Authors:
Lynne K Garrity-Ryan; Oak K Kim; Joan-Miquel Balada-Llasat; Victoria J Bartlett; Atul K Verma; Michael L Fisher; Cynthia Castillo; Warangkhana Songsungthong; S Ken Tanaka; Stuart B Levy; Joan Mecsas; Michael N Alekshun
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-07
Journal Detail:
Title:  Infection and immunity     Volume:  78     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-19     Completed Date:  2010-11-12     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4683-90     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Bacterial Agents / administration & dosage,  chemical synthesis,  chemistry,  pharmacology
Bacterial Proteins / antagonists & inhibitors*,  metabolism
Benzimidazoles / administration & dosage,  chemical synthesis,  chemistry,  pharmacology*
Cell Line
Disease Models, Animal
Female
Humans
Lung / microbiology
Macrophages / microbiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Pneumonia, Bacterial / drug therapy,  microbiology,  mortality,  pathology*
Transcription Factors / antagonists & inhibitors*,  metabolism
Treatment Outcome
Virulence
Yersinia pseudotuberculosis / drug effects*,  metabolism,  pathogenicity*
Yersinia pseudotuberculosis Infections / drug therapy,  microbiology,  mortality,  pathology*
Grant Support
ID/Acronym/Agency:
5R43AI058627-2/AI/NIAID NIH HHS; AI007422/AI/NIAID NIH HHS; AI056068/AI/NIAID NIH HHS; R25 GM066567/GM/NIGMS NIH HHS; R25GM066567/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Bacterial Proteins; 0/Benzimidazoles; 0/Transcription Factors; E24GX49LD8/benzimidazole
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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