Circumventing the PDR pathway in fungi.

Fig. 1. Circumventing the PDR pathway in fungi. (A) In cells with clinically important resistance to azole drugs, high-level transcription of PDR efflux-pump genes involves the recruitment of RNA polymerase II, which depends on a drug-induced interaction between the ScPdr1p/Pdr3p and mediator complexes. The efflux pumps reduce the intracellular concentration of the drug below that required to inhibit the azole target Erg11p, allowing normal cell growth. (B) Binding of a multifunctional azole to the XBD domain of ScPdr1p/Pdr3p blocks expression of the drug pumps responsible for multidrug efflux and inhibits drug efflux by occupying a binding site in residual efflux pumps. The intracellular concentration of the drug is thus sufficient to block ergosterol biosynthesis in the endoplasmic reticulum. Reduced ergosterol content of membranes, production of toxic methylated sterols, and oxidative damage kill the fungal cell. Alternatively, other antifungals directly inhibit the electrogenic plasma membrane H+-ATPase Pma1p, preventing the uptake of nutrients driven by the plasma membrane electrochemical gradient. The cells die rapidly because of a limited cellular energy supply and a loss of ion balance. Partial inhibition of Pma1p activity compromises the activity of both MFS and ABC transporters and increases the potency of azole drugs. [View Larger Version of this Image (55K GIF file)]