CELLULAR ACCUMULATION, LOCALIZATION, AND ACTIVITY OF A SYNTHETIC CYCLOPEPTAMINE IN FUNGI

A novel synthetic cyclopeptamine, A172013, rapidly accumulated by pass ive diffusion into Candida albicans CCH442. Drug influx could not be t otally facilitated by the membrane-bound target, beta-(1,3)-glucan syn thase, since accumulation was unsaturable at drug concentrations up to 10 mu g/ml (about 1.6 x 10(-7) molecules/cell), or 25 x MIC. About 55 and 23% of the cell-incorporated drug was associated with the cell wa ll and protoplasts, respectively, Isolated microsomes contained 95% of the protoplast-associated drug, which was fully active against glucan synthesis in vitro. Drug (0.1 mu g/ml) accumulation was rapid and com plete after 5 min in several fungi tested, including a lipopeptide/cyc lopeptamine-resistant strain of C. albicans (LP3-1). The compound pene trated to comparable levels in both yeast and hyphal forms of C. albic ans, and accumulation in Aspergillus niger was 20% that in C. albicans . These data indicated that drug-cell interactions were driven by the amphiphilic nature of the compound and that the cell wall served as a major drug reservoir.