A combined structure-activity and biophysical investigation of the cyclic lipopeptide tolaasin, the virulence factor causing brown blotch disease

01 November 2023 → 31 October 2027
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Spectroscopic methods
    • Medicinal and biomolecular chemistry not elsewhere classified
    • Bio-organic chemistry
    • Organic chemical synthesis
  • Medical and health sciences
    • Molecular biophysics
lipopeptide peptide-membrane interactions structure-activity relationships
Project description

Tolaasin, an 18 residue cyclic lipopeptide, is the main virulence factor of Pseudomonas tolaasii, and causes brown blotch disease in edible mushrooms. In addition to this antifungal activity, this secondary metabolite also display activity against Gram-positive, Gram-negative bacteria and cytotoxicity against MDA-MB-231 cancer cells. This wide targeting of cells is attributed to its membrane-lytic properties. While experimental data supports direct interaction with cellular membranes, molecular level understanding of the features of tolaasin involved and the underlying mechanisms ultimately leading to cell lysis are not well understood. In this project, a total synthesis route for tolaasin will be developed, followed by combined and comparative biological and biophysical evaluation of a series of specifically designed analogues. Of note, monitoring of leakage events and kinetics using ps-time-resolved fluorescence spectroscopy will provide unprecedented insight in the nature of tolaasin induced membrane perturbation, thus providing fundamental, molecular level understanding of the underlying mode of action.