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Discovery and Total Synthesis of Natural Cystobactamid Derivatives with Superior Activity against Gram‐Negative Pathogens
Author(s) -
Hüttel Stephan,
Testolin Giambattista,
Herrmann Jennifer,
Planke Therese,
Gille Franziska,
Moreno Maria,
Stadler Marc,
Brönstrup Mark,
Kirschning Andreas,
Müller Rolf
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201705913
Subject(s) - klebsiella oxytoca , pseudomonas aeruginosa , antibacterial activity , klebsiella pneumoniae , gram negative bacteria , drug discovery , biology , microbiology and biotechnology , scaffold , bacteria , human pathogen , chemistry , escherichia coli , bioinformatics , medicine , biochemistry , genetics , gene , biomedical engineering
Antibiotic discovery and development is challenging as chemical scaffolds of synthetic origin often lack the required pharmaceutical properties, and the discovery of novel ones from natural sources is tedious. Herein, we report the discovery of new cystobactamids with a significantly improved antibacterial profile in a detailed screening of myxobacterial producer strains. Some of these new derivatives display antibacterial activities in the low‐μg mL −1 range against Gram‐negative pathogens, including clinical isolates of Klebsiella oxytoca, Pseudomonas aeruginosa, and fluoroquinolone‐resistant Enterobacteriaceae, which were not observed for previously reported cystobactamids. Our findings provide structure–activity relationships and show how pathogen resistance can be overcome by natural scaffold diversity. The most promising derivative 861‐2 was prepared by total synthesis, enabling further chemical optimization of this privileged scaffold.