Leveraging Natural Product-Inspired Antifungals to Investigate the Mechanism of Action of Peniciaculin A

ChemMedChem. 2024 Dec 16;19(24):e202400500. doi: 10.1002/cmdc.202400500. Epub 2024 Oct 29.

Abstract

Ubiquinone mimics known as quinone outside inhibitors (QoIs) are one of the most prominent fungicides used to protect crops in the agricultural industry. Due to chemotype similarities with known QoIs, peniciaculin A, a triaryl natural product, was proposed to exhibit similar broad spectrum antifungal activity against phytopathogens. Instability of the tertiary alcohol and phenol motif, however, prompted exploration of the antifungal properties of simplified analogues to probe possible overlap in mechanism of action between the natural product and QoIs. Peniciaculin A inspired analogues mimicking known QoI scaffolds displayed broad spectrum antifungal activity while those containing scaffolds dissimilar to QoIs possessed negligible bioactivity. These activity profiles suggest peniciaculin A is likely acting as a QoI.

Keywords: Agriculture; Antifungal; Natural product; Quinone outside inhibitor; Simplified analogue.

MeSH terms

  • Antifungal Agents* / chemical synthesis
  • Antifungal Agents* / chemistry
  • Antifungal Agents* / pharmacology
  • Biological Products* / chemical synthesis
  • Biological Products* / chemistry
  • Biological Products* / pharmacology
  • Dose-Response Relationship, Drug
  • Microbial Sensitivity Tests*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Biological Products
  • Antifungal Agents