C. albicans cell wall stress responses and TOR signaling

Abstract Medical progress in many fields like oncology, transplantation, surgery, neonatology and rheumatology is hurt by the rising incidence of invasive fungal infections. Developing novel antifungal therapeutics is challenging because fungal and human cells share many homologous essential proteins. A novel approach to antifungal development could be to target non-conserved domains within conserved proteins, following detailed functional and structural characterization. On the other side, the cell wall has proven to be an excellent target: it commands a significant portion of signaling- and metabolic resources of the fungal cell, and the entire organelle is absent in humans. Identifying non-conserved regulatory elements in cell wall stress endurance, and testing non-conserved protein regions to identify targets of domain-based drug discovery, could expand the spectrum of targets for novel compounds that synergize with cell wall-active agents and protect them from resistance development. Mutants in Candida albicans Target of Rapamycin kinase 1 (Tor1) truncated for its least conserved region, N-terminal HEAT repeats, are hypersensitive to cell wall stress. Among transcripts aberrantly regulated in Tor1 N-terminal truncation mutants are a cell wall stress transcription factor and its putative regulator, both not present in humans. This transcription factor mediates C. albicans responses to echinocandins, antifungal agents that inhibit biosynthesis of the major structural polysaccharide in the fungal cell wall. We propose to identify targets in C. albicans cell wall stress endurance, whose inhibition potentiates echinocandins and protects them from resistance development, or has a cidal effect on its own. To this end, we will characterize a key cell wall stress transcription factor and its regulator, and two non-conserved regions of Kog1, the essential regulator in Target of Rapamycin Complex 1. Human oncologic target investigations and mechanistic analysis of neurodegenerative diseases combined, provide important background understanding of domain-based drug discovery and inhibitors of prion-like motifs. We intend to leverage this understanding towards a proof of the principle, that the paradigm for antifungal drug discovery can expand beyond the biosynthetic enzymes that currently are major targets, to include non-conserved regulatory elements which the fungus needs to protect its cell wall.