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Potential Novel Antibiotics from HTS Targeting the Virulence-regulating Transcription Factor, VirF, from Shigella flexneri
| Content Provider | PubMed Central |
|---|---|
| Author | Emanuele, Anthony A. Adams, Nancy E. Chen, Yi-chen Maurelli, Anthony T. Garcia, George A. |
| 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. |
| Related Links | http://dx.doi.org/10.1038/ja.2014.10 |
| Ending Page | 386 |
| Page Count | 8 |
| Starting Page | 379 |
| File Format | |
| ISSN | 00218820 |
| Journal | The Journal of antibiotics |
| Issue Number | 5 |
| Volume Number | 67 |
| Language | English |
| Publisher Date | 2014-05-01 |
| Access Restriction | Open |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Drug Discovery Pharmacology |
