Unlocking the therapeutic potential of the fungal cell wall: Clinical implications and drug resistance

Abstract

The cell wall of Candida albicans is essential for cellular survival. The wall is a rich polysaccharide and mannoprotein complex. During wall synthesis, the cell wall components-glucan, chitin and mannoproteins-are assembled and stabilised in the cell wall space by the action of cell wall-associated enzymes and structural wall proteins. Cell surface proteins are also important in C. albicans virulence. The components of the cell wall are unique to fungi, thus making the wall an attractive drug target. Echinocandins are antifungal drugs that inhibit the synthesis of cell wall b-1,3-D-glucan and are fungicidal to C. albicans. Echinocandin treatment, at sub-inhibitory concentrations, can result in a compensatory increase in wall chitin content and triggers the expression of mannoproteins whose activities remodel the wall. C. albicans cells with thicker cell walls and elevated chitin levels are less susceptible to echinocandin therapy. The development of a molecule that non-competitively inhibits chitin synthesis and/or impairs cell wall integrity response regulatory pathways may impact the cell wall in such a way that reduces its compensatory ability. This type of molecule may have a synergistic effect in combined therapy with other cell wall inhibitors such as b-1,3-D-glucan-targeting antifungal drugs for managing candidiasis infections. The synthesis and localisation of mannoproteins at the cell surface also provide an attractive cell wall target for future antifungal agents.