Engineering the biosynthesis of the polyketide-nonribosomal peptide collismycin A for generation of analogs with neuroprotective activity

Chem Biol. 2013 Aug 22;20(8):1022-32. doi: 10.1016/j.chembiol.2013.06.014. Epub 2013 Aug 1.


Collismycin A is a member of the 2,2'-bipyridyl family of natural products that shows cytotoxic activity. Structurally, it belongs to the hybrid polyketides-nonribosomal peptides. After the isolation and characterization of the collismycin A gene cluster, we have used the combination of two different approaches (insertional inactivation and biocatalysis) to increase structural diversity in this natural product class. Twelve collismycin analogs were generated with modifications in the second pyridine ring of collismycin A, thus potentially maintaining biologic activity. None of these analogs showed better cytotoxic activity than the parental collismycin. However, some analogs showed neuroprotective activity and one of them (collismycin H) showed better values for neuroprotection against oxidative stress in a zebrafish model than those of collismycin A. Interestingly, this analog also showed very poor cytotoxic activity, a feature very desirable for a neuroprotectant compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl / analogs & derivatives*
  • 2,2'-Dipyridyl / chemistry
  • 2,2'-Dipyridyl / metabolism
  • 2,2'-Dipyridyl / pharmacology
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Biosynthetic Pathways
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Genes, Bacterial
  • Genetic Engineering
  • Humans
  • Multigene Family
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism*
  • Neuroprotective Agents / pharmacology
  • Streptomyces / genetics*
  • Streptomyces / metabolism*
  • Zebrafish


  • Antineoplastic Agents
  • Neuroprotective Agents
  • collismycin A
  • 2,2'-Dipyridyl