Details
| Translated title of the contribution | Entdeckung und Totalsynthese von natürlichen Cystobactamid-Derivaten mit herausragender Aktivität gegen Gram-negative Pathogene |
|---|---|
| Original language | English |
| Pages (from-to) | 12760-12764 |
| Number of pages | 5 |
| Journal | Angewandte Chemie |
| Volume | 56 |
| Issue number | 41 |
| Publication status | Published - 20 Jul 2017 |
Abstract
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.
Keywords
- cystobactamids, gyrase inhibitors, myxobacteria, natural products, total synthesis
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
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In: Angewandte Chemie , Vol. 56, No. 41, 20.07.2017, p. 12760-12764.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Discovery and Total Synthesis of Natural Cystobactamid Derivatives with Superior Activity against Gram-Negative Pathogens
AU - Hüttel, Stephan
AU - Testolin, Giambattista
AU - Herrmann, Jennifer
AU - Planke, Therese
AU - Gille, Franziska
AU - Moreno, Maria
AU - Stadler, Marc
AU - Brönstrup, Mark
AU - Kirschning, Andreas
AU - Müller, Rolf
N1 - Funding information: This project was funded by the German Center for Infection Research (DZIF) to HZI and LUH and the Fonds der Chemischen Industrie. We thank Silke Reinecke and Viktoria Schmitt for excellent technical assistance and Dr. Kirsten Harmrolfs for careful proofreading of the manuscript.
PY - 2017/7/20
Y1 - 2017/7/20
N2 - 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.
AB - 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.
KW - cystobactamids
KW - gyrase inhibitors
KW - myxobacteria
KW - natural products
KW - total synthesis
UR - http://www.scopus.com/inward/record.url?scp=85028530229&partnerID=8YFLogxK
U2 - 10.1002/anie.201705913
DO - 10.1002/anie.201705913
M3 - Article
C2 - 28730677
AN - SCOPUS:85028530229
VL - 56
SP - 12760
EP - 12764
JO - Angewandte Chemie
JF - Angewandte Chemie
SN - 1433-7851
IS - 41
ER -