"'-----.....;

Figure 6 Membrane fluidity affects drug resistance conferred by Cdr1p. The right panel shows bars representing P values (fluorescence anisotropy). The increase in P value indicates higher membrane order (rigidity). Erg mutants expressing CDRl which have altered membrane fluidity show different susceptibilities to indicated drugs (bars shown on left panel) which is shown as diameter of inhibition zones. (From Ref. 149.)

effects on various functional aspects of Cdrlp. This study provided an understanding of how a yeast multidrug transporter protein, Cdrlp, could change its behavior in response to an altered membrane environment [149]. Earlier, Kaur et al., using the above-mentioned erg mutants, showed the effect of an altered lipid environment on the functioning of PDR5, a homolog of CDR} in S. cerevisiae [148]. Given the intimate relationship among P-gp, its hydrophobic substrates, and the surrounding membrane environment, it is expected that membrane lipids will have considerable influence over the functioning of Cdrlp. For instance, the floppase activity associated with Cdr1P could sustain the fluctuation in membrane fluidity of various erg mutants. The ability of the transformants to efflux drugs was, however, severely hampered since all became more sensitive to most of the tested drugs to which their wild type was resistant (Fig. 6). CaMdrlp, the MFS drug pump, also elicited reduced resistance and effluxing ability of methotrexate and fluconazole in cells with altered membrane fluidity. Our preliminary results suggest that azole-resistant isolates of C. albicans have altered membrane fluidity (Prasad et al., unpublished observation). Therefore, it is important to consider the physical state of membranes while assessing the functioning of membrane-bound drug transporters.