title: Cellular accumulation, localization, and activity of a synthetic cyclopeptamine in fungi.
abstract: A novel synthetic cyclopeptamine, A172013, rapidly accumulated by passive diffusion into Candida albicans CCH442. Drug influx could not be totally facilitated by the membrane-bound target, beta-(1,3)-glucan synthase, since accumulation was unsaturable at drug concentrations up to 10 microg/ml (about 1.6 x 10(-7) molecules/cell), or 25x MIC. About 55 and 23% of the cell-incorporated drug was associated with the cell wall and protoplasts, respectively. Isolated microsomes contained 95% of the protoplast-associated drug, which was fully active against glucan synthesis in vitro. Drug (0.1 microg/ml) accumulation was rapid and complete after 5 min in several fungi tested, including a lipopeptide/cyclopeptamine-resistant strain of C. albicans (LP3-1). The compound penetrated to comparable levels in both yeast and hyphal forms of C. albicans, 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.
authors.affiliation: Infectious Research Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. john.capobianco@abbott.com
authors.forename: J O
authors.initials: JO
authors.lastname: Capobianco
authors.forename: D
authors.initials: D
authors.lastname: Zakula
authors.forename: D J
authors.initials: DJ
authors.lastname: Frost
authors.forename: R C
authors.initials: RC
authors.lastname: Goldman
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: L L
authors.initials: LL
authors.lastname: Klein
authors.forename: P A
authors.initials: PA
authors.lastname: Lartey
mesh_terms: D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D005936:Glucans / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D011523:Protoplasts / Q000378:metabolism
chemical_list: C111080:A 172013; D005936:Glucans; D010456:Peptides, Cyclic