Cystobactamids: Myxobacterial Topoisomerase Inhibitors Exhibiting Potent Antibacterial Activity |
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Authors: | Dr Sascha Baumann Dr Jennifer Herrmann Dr Ritesh Raju Dipl‐Ing Heinrich Steinmetz Dr Kathrin I Mohr Dr Stephan Hüttel Dr Kirsten Harmrolfs Prof?Dr Marc Stadler Prof?Dr Rolf Müller |
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Institution: | 1. Abteilung Mikrobielle Naturstoffe, Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung, Universit?t des Saarlandes, Campus C2.3, 66123 Saarbrücken (Germany);2. Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover–Braunschweig (Germany);3. Mikrobielle Stammsammlung, Helmholtz Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig (Germany);4. Mikrobielle Wirkstoffe, Helmholtz Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig (Germany) |
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Abstract: | The development of new antibiotics faces a severe crisis inter alia owing to a lack of innovative chemical scaffolds with activities against Gram‐negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria‐derived cystobactamids 1 – 3 , which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low μg mL?1 range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self‐resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering. |
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Keywords: | antibiotics myxobacteria natural products NRPS topoisomerase inhibitors |
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