A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity

ACS Chem Biol. 2017 Nov 17;12(11):2815-2822. doi: 10.1021/acschembio.7b00677. Epub 2017 Oct 12.

Abstract

Thioviridamide is a structurally novel ribosomally synthesized and post-translational modified peptide (RiPP) produced by Streptomyces olivoviridis NA005001. It is characterized by a structure that features a series of thioamide groups and possesses potent antiproliferative activity in cancer cell lines. Its unusual structure allied to its promise as an anticancer compound led us to investigate the diversity of thioviridamide-like pathways across sequenced bacterial genomes. We have isolated and characterized three diverse members of this family of natural products. This characterization is supported by transformation-associated recombination cloning and heterologous expression of one of these compounds, thiostreptamide S4. Our work provides an insight into the diversity of this rare class of compound and indicates that the unusual N-terminus of thioviridamide is not introduced biosynthetically but is instead introduced during acetone extraction. A detailed analysis of the biological activity of one of the newly discovered compounds, thioalbamide, indicates that it is highly cytotoxic to cancer cells, while exhibiting significantly less activity toward a noncancerous epithelial cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Biosynthetic Pathways
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Genomics
  • Humans
  • Multigene Family*
  • Neoplasms / drug therapy
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / genetics
  • Peptides, Cyclic / pharmacology*
  • Streptomyces / chemistry
  • Streptomyces / genetics*
  • Streptomyces / metabolism
  • Thioamides / chemistry*
  • Thioamides / pharmacology*

Substances

  • Antineoplastic Agents
  • Peptides, Cyclic
  • Thioamides
  • thioviridamide