期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 56, 期 41, 页码 12760-12764出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201705913
关键词
cystobactamids; gyrase inhibitors; myxobacteria; natural products; total synthesis
资金
- German Center for Infection Research (DZIF)
- Fonds der Chemischen Industrie
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-gmL(-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.
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