A new class of inhibitors of the AraC family virulence regulator Vibrio cholerae ToxT
| Autor: | Evans O. Onyango, Ronald K. Taylor, Gabriela Kovacikova, Anne K Woodbrey, F. Jon Kull, Maria Pellegrini, Gordon W. Gribble |
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| Rok vydání: | 2017 |
| Předmět: |
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Molecular 0301 basic medicine Magnetic Resonance Spectroscopy Virulence Factors medicine.medical_treatment 030106 microbiology Molecular Conformation Regulator Virulence Disease Biology medicine.disease_cause Article Microbiology 03 medical and health sciences Bacterial Proteins medicine Humans Oral rehydration therapy Vibrio cholerae Transcription factor Binding Sites Multidisciplinary Cytarabine Clean water medicine.disease Cholera Anti-Bacterial Agents 3. Good health DNA-Binding Proteins Drug Design Protein Binding Transcription Factors |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep45011 |
| Popis: | Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primary V. cholerae virulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease. |
| Databáze: | OpenAIRE |
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