Isolation of a jadomycin incorporating L-ornithine, analysis of antimicrobial activity and jadomycin reactive oxygen species (ROS) generation in MDA-MB-231 breast cancer cells

J Antibiot (Tokyo). 2018 Aug;71(8):722-730. doi: 10.1038/s41429-018-0060-0. Epub 2018 Apr 26.

Abstract

Herein, we report the characterization and antimicrobial activity of a previously unreported jadomycin (1) obtained from a culture of S. venezuelae ISP5230 with L-ornithine (Orn). 1 arises from the rearrangement of a putative five-membered ring containing jadomycin incorporating Orn, whereby intramolecular attack of the E-ring carbonyl from the δ-NH2 group of the Orn side chain results in collapse of the oxazolone ring and formation of a stable six-membered lactam. This rearrangement produces a jadomycin with a 3a hemiaminal position that is susceptible to solvolysis. A structure-activity relationship is discussed based on the antimicrobial activity of 1 compared to previously reported jadomycins, providing evidence that the presence of a 3a hemiaminal enhances activity against Gram-positive bacteria. Additionally, assays to quantify reactive oxygen species (ROS) generation and cell viability were performed using a series of nine jadomycins. Compound 1 was found to produce the highest ROS activity and to possess the greatest cytotoxicity against MDA-MB-231 breast cancer cells.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Microbial Sensitivity Tests
  • Ornithine / chemistry
  • Reactive Oxygen Species / metabolism*
  • Staphylococcus / drug effects*
  • Streptomyces / metabolism
  • Structure-Activity Relationship
  • Triple Negative Breast Neoplasms / drug therapy*

Substances

  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Isoquinolines
  • Reactive Oxygen Species
  • Ornithine