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Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12760-12764. doi: 10.1002/anie.201705913. Epub 2017 Aug 29.

Discovery and Total Synthesis of Natural Cystobactamid Derivatives with Superior Activity against Gram-Negative Pathogens.

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Abteilung Mikrobielle Naturstoffe, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Helmholtz-Zentrum für Infektionsforschung, Universitätscampus E8 1, 66123, Saarbrücken, Germany.
Abteilung Mikrobielle Wirkstoffe, Helmholtz-Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
Deutsches Zentrum für Infektionsforschung, DZIF, Standort Hannover-Braunschweig, Germany.
Abteilung Chemische Biologie, Helmholtz-Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
Institut für Organische Chemie, Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.


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.


cystobactamids; gyrase inhibitors; myxobacteria; natural products; total synthesis


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