Synergistic activity of caspofungin and the plant defensin HsAFP1 or linear derivatives against Candida albicans biofilms

One of the reasons for the high mortality rate associated with fungal infections is the formation of biofilms by pathogenic fungi. Fungal biofilms are characterized by increased tolerance to various antifungal agents (antimycotics) and hence, are very difficult to eliminate. Only few conventional antimycotics can be used to treat those fungal biofilm-related infections. Therefore, there is a need for the identification and characterization of novel antifungal agents, which are also effective against fungal biofilms. Plant defensins, which are small (45-54 amino acids), highly structured antifungal peptides present in plants, are interesting candidates for the development of novel antifungal agents as they are generally non-toxic towards human cells, have a broad-spectrum antifungal activity, have a low in vitro frequency of resistance occurrence and preserve their antifungal activity in in vivo conditions. We recently demonstrated that plant defensins can inhibit Candida albicans biofilm formation and act synergistically with conventional antimycotics against biofilms. In view of the latter, we further focussed on the combination of the plant defensin from Heuchera sanguinea, HsAFP1, and caspofungin. Firstly, we performed structure-activity relationship studies of HsAFP1 by scanning its sequence with corresponding peptide fragments (16-24 amino acids) and identified peptide fragments with improved synergistic activity with caspofungin as compared to native HsAFP1. These data point to the potential of linear HsAFP1-derived peptide fragments as adjuvants for caspofungin antibiofilm activity. We are currently investigating the optimal HsAFP1-derived peptide length and sequence for synergistic activity with caspofungin, where after the best combination will be tested in vivo, using a rat subcutaneous catheter model.status: publishe