title: Discovery of novel antifungal (1,3)-beta-D-glucan synthase inhibitors.
abstract: The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell wall (1,3)-beta-D-glucan synthase such as lipopeptide pneumocandins and echinocandins as well as the glycolipid papulacandins have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas), a semisynthetic analogue of pneumocandin B(o), is being developed as a broad-spectrum parenteral agent for the treatment of aspergillosis and candidiasis. This and other lipopeptide antifungal agents have limited oral bioavailability. Thus, we have sought new chemical structures with the mode of action of lipopeptide antifungal agents but with the potential for oral absorption. Results of natural-product screening by a series of newly developed methods has led to the identification of four acidic terpenoid (1,3)-beta-D-glucan synthase inhibitors. Of the four compounds, the in vitro antifungal activity of one, enfumafungin, is comparable to that of L-733560, a close analogue of MK-0991. Like the lipopeptides, enfumafungin specifically inhibits glucan synthesis in whole cells and in (1,3)-beta-D-glucan synthase assays, alters the morphologies of yeasts and molds, and produces a unique response in Saccharomyces cerevisiae strains with point mutations in FKS1, the gene which encodes the large subunit of glucan synthase.
authors.affiliation: Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. jan_onishi@merck.com
authors.forename: J
authors.initials: J
authors.lastname: Onishi
authors.forename: M
authors.initials: M
authors.lastname: Meinz
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: J
authors.initials: J
authors.lastname: Curotto
authors.forename: S
authors.initials: S
authors.lastname: Dreikorn
authors.forename: M
authors.initials: M
authors.lastname: Rosenbach
authors.forename: C
authors.initials: C
authors.lastname: Douglas
authors.forename: G
authors.initials: G
authors.lastname: Abruzzo
authors.forename: A
authors.initials: A
authors.lastname: Flattery
authors.forename: L
authors.initials: L
authors.lastname: Kong
authors.forename: A
authors.initials: A
authors.lastname: Cabello
authors.forename: F
authors.initials: F
authors.lastname: Vicente
authors.forename: F
authors.initials: F
authors.lastname: Pelaez
authors.forename: M T
authors.initials: MT
authors.lastname: Diez
authors.forename: I
authors.initials: I
authors.lastname: Martin
authors.forename: G
authors.initials: G
authors.lastname: Bills
authors.forename: R
authors.initials: R
authors.lastname: Giacobbe
authors.forename: A
authors.initials: A
authors.lastname: Dombrowski
authors.forename: R
authors.initials: R
authors.lastname: Schwartz
authors.forename: S
authors.initials: S
authors.lastname: Morris
authors.forename: G
authors.initials: G
authors.lastname: Harris
authors.forename: A
authors.initials: A
authors.lastname: Tsipouras
authors.forename: K
authors.initials: K
authors.lastname: Wilson
authors.forename: M B
authors.initials: MB
authors.lastname: Kurtz
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D054714:Echinocandins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics; D005936:Glucans / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D012440:Saccharomyces / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D005936:Glucans; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase; C091618:FKS1 protein, S cerevisiae