title: Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity.
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.
authors.affiliation: Abteilung Mikrobielle Naturstoffe, Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung, Universität des Saarlandes, Campus C2.3, 66123 Saarbrücken (Germany); Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig (Germany).
authors.forename: Sascha
authors.initials: S
authors.lastname: Baumann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.forename: Ritesh
authors.initials: R
authors.lastname: Raju
authors.forename: Heinrich
authors.initials: H
authors.lastname: Steinmetz
authors.forename: Kathrin I
authors.initials: KI
authors.lastname: Mohr
authors.forename: Stephan
authors.initials: S
authors.lastname: Hüttel
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harmrolfs
authors.forename: Marc
authors.initials: M
authors.lastname: Stadler
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry* / Q000494:pharmacology; D001216:Asparagine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009231:Myxococcales / Q000201:enzymology*; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010453:Peptide Synthases / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009574:Nitro Compounds; D059003:Topoisomerase Inhibitors; C000600617:cystobactamid 919-2; D001216:Asparagine; D004264:DNA Topoisomerases, Type I; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase
keywords: NRPS; antibiotics; myxobacteria; natural products; topoisomerase inhibitors