Journal
CHEMMEDCHEM
Volume 14, Issue 11, Pages 1074-1078Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900193
Keywords
antibiotics; drug discovery; small molecules; synergism; synthesis
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [CRC1093, EH100/16-1, KA2894/4-1]
- Ministry of Innovation, Research and Science (MIWF) of the province North-Rhine Westphalia (NRW), Germany (Forderkennzeichen) [40001210]
- Boehringer Ingelheim Foundation (Plus-3 grant) [390677874]
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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 sigma E 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.
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