The yeast multidrug resistance pump, Pdr5p, confers reduced drug resistance in erg mutants of Saccharomyces cerevisiae

Mutants of Saccharomyces cerevisiae bearing lesions in the ergosterol biosy nthetic pathway exhibit a pleiotropic drug-sensitive phenotype. This has be en reported to result from an increased permeability of the membranes of th e mutant strains to different drugs. As disruption of the yeast multidrug r esistance protein, Pdr5p, results in a similar pleiotropic drug-sensitive p henotype, the possibility that Pdr5p may be functioning with a reduced effi ciency in these altered sterol backgrounds was examined. To do this, the fu nction of Pdr5p in isogenic strains of S. cerevisiae that have disruptions in the late stages of the ergosterol biosynthesis pathway (ERG6, ERG2, ERG3 , ERG4) was studied. A reduced ability of Pdr5p to confer resistance to dif ferent drugs in these strains was observed, which did not appear to be depe ndent solely on the permeability of the membrane towards the drug. A simult aneous examination was made of how the lipid composition might be altering the efficiency of Pdr5p by similar studies in strains lacking phosphatidyls erine synthase (encoded by CHO1). The results indicated that the drug sensi tivity of the erg strains is, to a significant extent, a result of the redu ced efficiency of the Pdr5p efflux pump, and that the membrane environment plays an important role in determining the drug resistance conferred by Pdr 5p.