Pyonitrins A-D: Chimeric Natural Products Produced by Pseudomonas protegens

J Am Chem Soc. 2019 Oct 30;141(43):17098-17101. doi: 10.1021/jacs.9b09739. Epub 2019 Oct 16.

Abstract

Bacterial symbionts frequently provide chemical defenses for their hosts, and such systems can provide discovery pathways to new antifungals and structurally intriguing metabolites. This report describes a small family of naturally occurring small molecules with chimeric structures and a mixed biosynthesis that features an unexpected but key nonenzymatic step. An insect-associated Pseudomonas protegens strain's activity in an in vivo murine candidiasis assay led to the discovery of a family of highly hydrogen-deficient metabolites. Bioactivity- and mass-guided fractionation led to the pyonitrins, highly complex aromatic metabolites in which 10 of the 20 carbons are quaternary, and 7 of them are contiguous. The P. protegens genome revealed that the production of the pyonitrins is the result of a spontaneous reaction between biosynthetic intermediates of two well-studied Pseudomonas metabolites, pyochelin and pyrrolnitrin. The combined discovery of the pyonitrins and identification of the responsible biosynthetic gene clusters revealed an unexpected biosynthetic route that would have prevented the discovery of these metabolites by bioinformatic analysis alone.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antifungal Agents / chemistry
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biological Products / chemistry*
  • Biological Products / metabolism*
  • Biological Products / pharmacology
  • Biosynthetic Pathways / genetics
  • Candida albicans / drug effects
  • Candidiasis / drug therapy
  • Candidiasis / microbiology
  • Chromatography, High Pressure Liquid
  • Drug Evaluation, Preclinical / methods
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Structure
  • Phenols / metabolism
  • Pseudomonas / genetics
  • Pseudomonas / metabolism*
  • Pyrrolnitrin / biosynthesis
  • Thiazoles / metabolism

Substances

  • Antifungal Agents
  • Bacterial Proteins
  • Biological Products
  • Phenols
  • Thiazoles
  • pyochelin
  • Pyrrolnitrin

Supplementary concepts

  • Pseudomonas protegens