Coordinate control of lipid composition and drug transport activities is required for normal multidrug resistance in fungi

Abstract

Pathogenic fungi present a special problem in the clinic as the range of drugs that can be used to treat these types of infections is limited. This situation is further complicated by the presence of robust inducible gene networks encoding different proteins that confer tolerance to many available antifungal drugs. The transcriptional control of these multidrug resistance systems in several key fungi will be discussed. Experiments in the non-pathogenic Saccharomyces cerevisiae have provided much of our current understanding of the molecular framework on which fungal multidrug resistance is built. More recent studies on the important pathogenic Candida species, Candida albicans and Candida glabrata, have provided new insights into the organization of the multidrug resistance systems in these organisms. We will compare the circuitry of multidrug resistance networks in these three organisms and suggest that, in addition to the well-accepted drug efflux activities, the regulation of membrane composition by multidrug resistance proteins provides an important contribution to the resistant phenotypes observed.

Figure 1. Control of multidrug resistance in S. cerevisiae

Pathways regulating the expression of multidrug resistance genes are depicted here. Positive interactions are denoted by an arrow while negative effect are indicate by a T-bar. Loss of the mitochondrial DNA gives rise to ρ⁰ cells that activate ScPdr3 post-translationally. ScYrr1 binds to its target element which is juxtaposed with the Pdr1/3 response elements (PDREs) in some promoters. See the text for details.

Figure 2. Control of multidrug resistance in Candida species

Similar transcriptional control mechanisms in Candida albicans (top) and Candida glabrata (bottom) are shown. No mitochondrial input has yet been described for regulation of multidrug resistance in C. albicans.

Figure 3. Regulation of multidrug resistance at the plasma membrane

S. cerevisiae is used as the prototype for the various mechanisms that may act to control drug entry into fungal cells. Drugs can enter the cell in many cases by diffusion and are removed by the direct action of multidrug transporters like Pdr5 but also other membrane transporter proteins (blue box). ScPdr5 has at least one other activity which is to control phospholipid distribution across the plasma membrane. Sphingolipid distribution is also asymmetric across the plasma membrane with the majority of these lipids located in the outer leaflet. Control of the lipid composition of the plasma membrane is likely to influence the activity of embedded proteins.