Abstract |
VirF is an AraC-type transcriptional regulator responsible for activating the transcription of virulence genes required for the intracellular invasion and cell-to-cell spread of Shigella flexneri. Gene disruption studies have validated VirF as a potential target for an anti-virulence therapy to treat shigellosis by determining that VirF is necessary for virulence, but not required for bacterial viability. Using a bacteria-based, β- galactosidase reporter assay we completed a high-throughput screening (HTS) campaign monitoring VirF activity in the presence of over 140,000 small molecules. From our screening campaign, we identified five lead compounds to pursue in tissue culture-based invasion and cell-to-cell spread assays, and toxicity screens. Our observations of activity in these models for infection have validated our approach of targeting virulence regulation and have allowed us to identify a promising chemical scaffold from our HTS for hit-to-lead development. Interestingly, differential effects on invasion versus cell-to-cell spread suggest that the compounds' efficacies may depend, in part, on the specific promoter that VirF is recognizing.
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Authors | Anthony A Emanuele, Nancy E Adams, Yi-Chen Chen, Anthony T Maurelli, George A Garcia |
Journal | The Journal of antibiotics
(J Antibiot (Tokyo))
Vol. 67
Issue 5
Pg. 379-86
(May 2014)
ISSN: 1881-1469 [Electronic] England |
PMID | 24549153
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anti-Bacterial Agents
- Indicators and Reagents
- Interferon Regulatory Factors
- Viral Proteins
- Virulence Factors
- viral interferon regulatory factors
- beta-Galactosidase
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Topics |
- Algorithms
- Anti-Bacterial Agents
(isolation & purification, pharmacology)
- Data Interpretation, Statistical
- Genes, Reporter
(genetics)
- HeLa Cells
- High-Throughput Screening Assays
(methods)
- Humans
- Indicators and Reagents
- Interferon Regulatory Factors
(drug effects)
- Microbial Sensitivity Tests
- Plasmids
(genetics)
- Reproducibility of Results
- Shigella flexneri
(drug effects, genetics, growth & development)
- Viral Proteins
(drug effects)
- Virulence
(genetics)
- Virulence Factors
- beta-Galactosidase
(genetics)
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