Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity

Angew Chem Int Ed Engl. 2014 Dec 22;53(52):14605-9. doi: 10.1002/anie.201409964. Epub 2014 Dec 15.


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.

Keywords: NRPS; antibiotics; myxobacteria; natural products; topoisomerase inhibitors.

MeSH terms

  • Anti-Bacterial Agents / biosynthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Asparagine / analogs & derivatives*
  • Asparagine / chemical synthesis
  • Asparagine / chemistry
  • Asparagine / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / metabolism
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Microbial Sensitivity Tests
  • Myxococcales / enzymology*
  • Nitro Compounds / chemical synthesis
  • Nitro Compounds / chemistry*
  • Nitro Compounds / pharmacology
  • Peptide Synthases / metabolism
  • Topoisomerase Inhibitors / chemistry*
  • Topoisomerase Inhibitors / metabolism
  • Topoisomerase Inhibitors / pharmacology


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Nitro Compounds
  • Topoisomerase Inhibitors
  • cystobactamid 919-2
  • Asparagine
  • DNA Topoisomerases, Type I
  • Peptide Synthases
  • non-ribosomal peptide synthase