title: Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from the Fusarium larvarum complex and other Hypocrealean fungi.
abstract: Evaluation of fungal fermentation extracts with whole cell Candida albicans activity resulted in the identification of a novel class of isoxazolidinone-containing metabolites named parnafungins. Chemical-genetic profiling with the C. albicans fitness test identified the biochemical target as inhibition of polyadenosine polymerase, a component of the mRNA cleavage and polyadenylation complex. Parnafungins were discovered from fermentation extracts of fungi resembling F. larvarum isolated from plants, plant litter and lichens. Furthermore authentic strains of F. larvarum var. larvarum and F. larvarum var. rubrum could be induced to produce parnafungins and their degradation products in low titers. Relationships among strains of the F. larvarum complex (FLC), including parnafungin-producing strains, were examined by cladistic analyses of rDNA, mitochondrial rDNA, and two protein-coding genes, comparisons of antifungal activity and antifungal metabolite profiles, and morphological phenotypes. Integrated analyses of these data led to the conclusion that the diversity within the FLC exceeded the one-to-one correspondence between F. larvarum and its teleomorph Cosmospora aurantiicola. Based on multiple gene sequence analyses, strains of the FLC formed a monophyletic clade inclusive of the parnafungin-producing strains. The FLC, including newly discovered parnafungin-producing strains, could be resolved into at least six different lineages, possibly representing cryptic' species, of which one was not fully resolved from F. larvarum var. rubrum. Fusarium larvarum var. rubrum represents a species distinct from var. larvarum. Finally we report that two other species from the Hypocreales, Trichonectria rectipila and Cladobotryum pinarense, are able to produce parnafungins and their open-ring forms.
authors.affiliation: Centro de Investigación Básica, Merck, Sharp & Dohme de España S. A., Josefa Valcárcel 38, Madrid, E-28027, Spain. gerald.bills@medinaandalucia.es
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Platas
authors.forename: David P
authors.initials: DP
authors.lastname: Overy
authors.forename: Javier
authors.initials: J
authors.lastname: Collado
authors.forename: Asunción
authors.initials: A
authors.lastname: Fillola
authors.forename: María Rosa
authors.initials: MR
authors.lastname: Jiménez
authors.forename: Jesús
authors.initials: J
authors.lastname: Martín
authors.forename: Antonio González
authors.initials: AG
authors.lastname: del Val
authors.forename: Francisca
authors.initials: F
authors.lastname: Vicente
authors.forename: J Rubén
authors.initials: JR
authors.lastname: Tormo
authors.forename: Fernando
authors.initials: F
authors.lastname: Peláez
authors.forename: Kathleen
authors.initials: K
authors.lastname: Calati
authors.forename: Guy
authors.initials: G
authors.lastname: Harris
authors.forename: Craig
authors.initials: C
authors.lastname: Parish
authors.forename: Deming
authors.initials: D
authors.lastname: Xu
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
mesh_terms: D004271:DNA, Fungal / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D005670:Fusarium / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D005800:Genes, Fungal; D014644:Genetic Variation; D013058:Mass Spectrometry; D023303:Oxazolidinones / Q000378:metabolism*; D010802:Phylogeny; D026723:Polyadenylation; D012333:RNA, Messenger / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013172:Spores, Fungal / Q000166:cytology
chemical_list: D004271:DNA, Fungal; D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; D023303:Oxazolidinones; D012333:RNA, Messenger