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ChemMedChem. 2019 Jun 5;14(11):1074-1078. doi: 10.1002/cmdc.201900193. Epub 2019 Apr 24.

Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action.

Author information

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
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.
7
Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Paracelsus Medical University, Prof.-Ernst-Nathan-Straße 1, 90419, Nürnberg, 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

PMID:
30945468
DOI:
10.1002/cmdc.201900193

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