Antifungal therapeutic potential of Candida albicans Fun30: screening and validation of novel inhibitors against Candida albicans

Abstract

WHO has listed Candida albicans as a fungal pathogen of priority. With the increasing incidence of C. albicans infection and limited treatment strategies, the identification of new drug targets and inhibitor molecules is of global concern. ATP-dependent chromatin remodelling proteins play a crucial role in regulating gene expression. Fun30 from C. albicans (CaFun30) mediates DNA end-resection during DNA double-strand break repair. It also transcriptionally co-regulates the expression of DNA damage response genes and genes involved in white-opaque switching. The gene is not essential for viability; however, the null mutant shows increased sensitivity to genotoxic agents. We hypothesised that the protein could be a potential therapeutic target against C. albicans. The structural model of CaFun30 was generated using homology modelling. Screening of a small molecule library identified 10 potential molecules, of which F1853-0039 was found as the lead inhibitor candidate. In vitro studies showed that the molecule had an MIC in the micromolar range against C. albicans with minimal effect on human THP-1 cells. Finally, coculture experiments showed that the inhibitor molecule prevented the formation of hyphae of C. albicans upon infecting THP-1 cells leading us to conclude that CaFun30 could potentially be developed as a therapeutic target against C. albicans.