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Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action |
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| Authors: | Dr. Jens Bongard Dr. Anna Laura Schmitz Dr. Alex Wolf Dr. Gunther Zischinsky Dr. Michel Pieren Birgit Schellhorn Dr. Kenny Bravo-Rodriguez Dr. Jasmin Schillinger Dr. Uwe Koch Dr. Peter Nussbaumer Dr. Bert Klebl Prof. Dr. Jörg Steinmann Prof. Dr. Jan Buer Prof. Elsa Sanchez-Garcia Prof. Dr. Michael Ehrmann Prof. Dr. Markus Kaiser |
| Affiliation: | 1. Microbiology, Faculty of Biology, Center of Medical Biotechnology, University Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany;2. Chemical Biology, Faculty of Biology, Center of Medical Biotechnology, University Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany;3. Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany;4. BioVersys AG, Hochbergerstrasse 60C, 4057 Basel, Switzerland;5. Microbiology, Faculty of Biology, Center of Medical Biotechnology, University Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany Computational Biochemistry, Faculty of Biology & Faculty of Chemistry, Center of Medical Biotechnology, University Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany;6. University Hospital Essen, University of Duisburg-Essen, Institute of Medical Microbiology, Hufelandstr. 55, 45122 Essen, Germany Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Paracelsus Medical University, Prof.-Ernst-Nathan-Straße 1, 90419 Nürnberg, Germany;7. University Hospital Essen, University of Duisburg-Essen, Institute of Medical Microbiology, Hufelandstr. 55, 45122 Essen, Germany;8. Computational Biochemistry, Faculty of Biology & Faculty of Chemistry, Center of Medical Biotechnology, University Duisburg-Essen, Universitätsstr. 2, 45117 Essen, Germany |
| Abstract: | Despite the availability of hundreds of antibiotic drugs, infectious diseases continue to remain one of the most notorious health issues. In addition, the disparity between the spread of multidrug-resistant pathogens and the development of novel classes of antibiotics exemplify an important unmet medical need that can only be addressed by identifying novel targets. Herein we demonstrate, by the development of the first in vivo active DegS inhibitors based on a pyrazolo[1,5-a]-1,3,5-triazine scaffold, that the serine protease DegS and the cell envelope stress-response pathway σE represent a target for generating antibiotics with a novel mode of action. Moreover, DegS inhibition is synergistic with well-established membrane-perturbing antibiotics, thereby opening promising avenues for rational antibiotic drug design. |
| Keywords: | antibiotics drug discovery small molecules synergism synthesis |