Search for antifungal compounds using a susceptible strain of Candida albicans and in vivo activity with the Galleria mellonella model

Invasive fungal infections have dramatically increased over the last 20 years. They became a major cause of nosocomial infections in developed countries making urgent the need of new antifungal drugs [1]. In this context, NPs have a high potential to become interesting leads for drug discovery. In our search for new antifungal compounds, four South American plants extracts were selected based on their in vitro antifungal activity. These extracts presented interesting activity against Candida albicans in a bioautography assay using hypersusceptible engineered strain [2]. This mutant strain was used in order to isolate the minor active constituent which would not have been detected otherwise. Bioassay-guided microfractionation was undertaken using HPLC to localize the active compounds. Different zones of the HPLC-UV chromatogram were linked to antifungal activities. In parallel to this HPLC-based activity profiling, UHPLC-TOF-HRMS was used for the early identification of some of the compounds present. The targeted isolation of the active compounds was performed by MPLC-UV and further semi-preparative HPLC steps. Structures of the isolated compounds were elucidated by spectroscopic methods including UV, NMR, MS and HRMS. Their absolute configuration was elucidated by ECD. Some of them were new NPs. Belong the fourteen isolated compounds, three saponins, two terpenes and two anthraquinones were specifically active against Candida spp with MIC below 32 µg/mL. The antifungal properties were also evaluated against biofilms of C. albicans and in vivo activity was assessed using the Galleria mellonella model.

References:

[1] Ostrosky-Zeichner L, Casadevall A, Galgiani J. N, Odds F. C, Rex J. H. An insight into the antifungal pipeline: selected new molecules and beyond. Nat Rev Drug Discov 2010; 9, 719 – 727.