title: Arundifungin, a novel antifungal compound produced by fungi: biological activity and taxonomy of the producing organisms.
abstract: Echinocandins, the lipopeptide class of glucan synthase inhibitors, are an alternative to ergosterol-synthesis inhibitors to treat candidiasis and aspergillosis. Their oral absorption, however, is low and they can only be used parenterally. During a natural product screening program for novel types of glucan synthesis inhibitors with improved bioavailability, a fungal extract was found that inhibited the growth of both a wild-type Saccharomyces cerevisiae strain and the null mutant of the FKS1 gene (fks1::HIS). The mutant strain was more sensitive to growth inhibition, suggesting that the fungal extract could contain an inhibitor of glucan synthesis. A novel acidic steroid, named arundifungin, was purified from a fungal extract obtained from a liquid culture of Arthrinium arundinis collected in Costa Rica. Arundifungin caused the same pattern of hallmark morphological alterations in Aspergillus fumigatus hyphae as echinocandins, further supporting the idea that arundifungin belongs to a new class of glucan synthesis inhibitors. Moreover, its antifungal spectrum was comparable to those of echinocandins and papulacandins, preferentially inhibiting the growth of Candida and Aspergillus strains, with very poor activity against Cryptococcus. Arundifungin was also detected in nine other fungal isolates which were ecologically and taxonomically unrelated, as assessed by sequencing of the ITS1 region. Further, it was also found in two more Arthrinium spp from tropical and temperate regions, in five psychrotolerant conspecific isolates collected on Macquarie Island (South Pacific) and belonging to the Leotiales, and in two endophytes collected in central Spain (a sterile fungus belonging to the Leotiales and an undetermined coelomycete).
authors.affiliation: Centro de Investigación Básica - Natural Products Drug Discovery, Merck Research Laboratories, Merck, Sharp & Dohme de España, Madrid, Spain. angeles_cabello@merck.com
authors.forename: M A
authors.initials: MA
authors.lastname: Cabello
authors.forename: G
authors.initials: G
authors.lastname: Platas
authors.forename: J
authors.initials: J
authors.lastname: Collado
authors.forename: M T
authors.initials: MT
authors.lastname: Díez
authors.forename: I
authors.initials: I
authors.lastname: Martín
authors.forename: F
authors.initials: F
authors.lastname: Vicente
authors.forename: M
authors.initials: M
authors.lastname: Meinz
authors.forename: J C
authors.initials: JC
authors.lastname: Onishi
authors.forename: C
authors.initials: C
authors.lastname: Douglas
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: M B
authors.initials: MB
authors.lastname: Kurtz
authors.forename: R E
authors.initials: RE
authors.lastname: Schwartz
authors.forename: G F
authors.initials: GF
authors.lastname: Bills
authors.forename: R A
authors.initials: RA
authors.lastname: Giacobbe
authors.forename: G K
authors.initials: GK
authors.lastname: Abruzzo
authors.forename: A M
authors.initials: AM
authors.lastname: Flattery
authors.forename: L
authors.initials: L
authors.lastname: Kong
authors.forename: F
authors.initials: F
authors.lastname: Peláez
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005658:Fungi / Q000145:classification* / Q000187:drug effects* / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D008565:Membrane Proteins; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology; D014315:Triterpenes
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes; D014315:Triterpenes; C458839:arundifungin; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase