Candida albicans is the most common human fungal pathogen. It is usually found in most healthy humans as a non-pathogenic commensal; however, it can develop into life-threatening mycoses in immunocompromised subjects, such as patients undergoing AIDS therapy, or patients subjected to chemotherapy. In addition to that, C. albicans can also adhere to plastics and form biofilms.
Treatments with the commonly available antifungals are hampered by the frequent onset of resistance of the fungus or by intrinsic toxicity of the drugs (amphotericin B). Furthermore, C. albicans biofilms are very resistant to antifungals; hence the wide interest in the development of novel antifungals.
Using TANGO, a statistical mechanics algorithm that predicts protein aggregation, developed by the VIB-SWITCH Laboratory, we are currently testing the possibility to obtain functional protein knock-outs by triggering aggregation, and subsequent inactivation, of a given protein in vivo. Our method is based on the overexpression of short peptides from the target protein with a high predicted propensity to aggregation.
We obtained encouraging results, albeit preliminary, targeting Gsc1p (Fks1p), an essential protein required for cell-wall biosynthesis, and Als3p, an adhesin important for biofilm formation. Conditional overexpression of a 17-mer peptide from Gsc1p fused to Gfp, in particular, caused a dramatic negative effect on growth of C. albicans and the appearance of aggregated Gfp clumps in correspondence of the cell periphery.
In conclusion, our novel approach to the research and development of antifungals would target inactivation of one or more fungal proteins in a direct way, thus eliminating the most limiting factors in antifungal development: synthesis of a large number of chemicals and screening for those chemicals interfering with the target protein(s). In addition, the possible development of peptide-based drugs should minimize the risk of intrinsic toxicity.