Antifungal polybrominated proxyphylline derivative induces Candida albicans calcineurin stress response in Galleria mellonella

Bioorg Med Chem Lett. 2020 Dec 1;30(23):127545. doi: 10.1016/j.bmcl.2020.127545. Epub 2020 Sep 12.

Abstract

Candida albicans CNB1 plays a role in the response in vitro and in vivo to stress generated by PB-WUT-01, namely 1,3-dimethyl-7-(2-((1-(3-(perbromo-2H-benzo[d][1,2,3]triazol-2-yl)propyl)-1H-1,2,3-triazol-4-yl)methoxy)propyl)-1H-purine-2,6(3H,7H)-dione. The antifungal mechanism involved the calcineurin pathway-regulated genes SAP9-10. Galleria mellonella treated with PB-WUT-01 (at 0.64 µg/mg) showed limited candidiasis and remained within the highest survival rates. The molecular mode of action of PB-WUT-01 was rationalized by in silico docking studies toward both human and C. albicans calcineurin A (CNA) and calcineurin B (CNB) complexes, respectively. PB-WUT-01 acting as a calcineurin inhibitor in the C. albicans cells enhances the cells' susceptibility. Therefore it could be a suitable alternative treatment in patients with candidiasis.

Keywords: Antifungal activity; C. albicans; Calcineurin pathway; Molecular docking; Proxyphylline-TBBt derivative.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / metabolism
  • Antifungal Agents / pharmacology*
  • Apoptosis / drug effects
  • Aspartic Acid Endopeptidases / metabolism
  • Biofilms / drug effects
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors / chemical synthesis
  • Calcineurin Inhibitors / metabolism
  • Calcineurin Inhibitors / pharmacology*
  • Candida albicans / drug effects*
  • Candida albicans / physiology
  • Chlorocebus aethiops
  • Fungal Proteins / metabolism
  • Larva / drug effects
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation
  • Moths
  • Protein Binding
  • Theophylline / analogs & derivatives*
  • Theophylline / metabolism
  • Theophylline / pharmacology
  • Vero Cells

Substances

  • Antifungal Agents
  • Calcineurin Inhibitors
  • Fungal Proteins
  • proxyphylline
  • Theophylline
  • Calcineurin
  • Aspartic Acid Endopeptidases
  • Sap10 protein, Candida albicans
  • Sap9 protein, Candida albicans