Unusual susceptibility of a multidrug-resistant yeast strain to peptidic antifungals

The susceptibility of Saccharomyces cerevisiae JG436 multidrug transporter deletion mutant, Delta pdr5, to several antifungal agents was compared to t hat of JG436-derived JGCDR1 and JGCaMDR1 transformants, harboring the CDR1 and CaMDR1 genes, encoding the main drug-extruding membrane proteins of Can dida albicans. The JGCDR1 and JGCaMDR1 yeasts demonstrated markedly diminis hed susceptibility to the azole antifungals, terbinafine and cycloheximide, while that to amphotericin B was unchanged, Surprisingly, JGCDR1 but not J GCaMDR1 cells showed enhanced susceptibility to peptidic antifungals, ratio nally designed compounds containing inhibitors of glucosamine-6-phosphate s ynthase. It was found that these antifungal oligopeptides, as well as model oligopeptides built of proteinogenic amino acids, were not effluxed from J GCDR1 cells, Moreover, they were taken up by these cells at rates two to th ree times higher than by JG436. The tested oligopeptides were rapidly cleav ed to constitutive amino acids by cytoplasmic peptidases, Studies on the me chanism of the observed phenomenon suggested that an additive proton motive force generated by Cdr1p stimulated uptake of oligopeptides into JGCDR1 ce lls, thus giving rise to the higher antifungal activity of FMDP [N-3-(4-met hoxyfumaroyl)-L-2,3-diaminopropanoic acid]-peptides.