Fig 1.
A model illustrating cell wall architecture and antifungal agents targeting specific components of the cell wall (A). Several antifungal agents are available that target the cell wall, but only the echinocandins have been licenced for the treatment of fungal infections; research into β-1,6-glucan inhibitor has been relatively unsuccessful. Cell wall integrity pathway leading to caspofungin drug tolerance (B). The Pkc pathway is activated in response to damage to the cell wall caused by inhibition of β-1,3-glucan synthesis by echinocandins. The signal that cell wall is weakened is transduced by membrane-bound mechanosensors such as members of the Wsc family, to activate Rho1. Rho1 activates Pkc1 which in turn activates the downstream MAP kinase cascade leading to the phosphorylation of Mkc1. A number of transcription factors are then activated including Cas5 and Rlm1 that switch on the expression of genes involved in cell wall construction and remodelling. The calcium signalling pathway is involved in cell wall salvage response. The pathway is activated by Ca2+ that enters the cell through membrane-localised channels or is released from intracellular stores. Ca2+ binds to and activates calmodulin (Cmd1). Cmd1 activates the phosphatase calcineurin, which is made up of 2 subunits Cna1 and Cnb1. Calcineurin dephosphorylates the transcription factor Crz1. Crz1 then moves into the nucleus and induces the expression of genes through binding to CDREs within their promoter sequences. The calcium signalling pathway regulates CHS genes. CDREs, calcium-dependent response elements; CWPGs, cell wall protein genes; GPI, glycosylphosphatidylinositol.