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Chemical Validation of DegS As a Target for the Development of Antibiotics with a Novel Mode of Action
Author(s) -
Bongard Jens,
Schmitz Anna Laura,
Wolf Alex,
Zischinsky Gunther,
Pieren Michel,
Schellhorn Birgit,
BravoRodriguez Kenny,
Schillinger Jasmin,
Koch Uwe,
Nussbaumer Peter,
Klebl Bert,
Steinmann Jörg,
Buer Jan,
SanchezGarcia Elsa,
Ehrmann Michael,
Kaiser Markus
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900193
Subject(s) - antibiotics , mode of action , computational biology , drug development , drug design , rational design , biology , drug , chemistry , pharmacology , microbiology and biotechnology , bioinformatics , biochemistry , genetics
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.