Chemical Epigenetics Alters the Secondary Metabolite Composition of Guttate Excreted by an Atlantic-Forest-Soil-Derived Penicillium citreonigrum

Abstract

Chemical epigenetic manipulation of Penicillium citreonigrum led to profound changes in the secondary metabolite profile of its guttate. While guttate from control cultures exhibited a relatively simple assemblage of secondary metabolites, the guttate collected from cultures treated with 50 μM 5-azacytidine (a DNA methyltransferase inhibitor) were highly enriched in compounds representing at least three distinct biosynthetic families. The metabolites obtained from the fungus included six azaphilones (sclerotiorin (1), sclerotioramine (6), ochrephilone (2), dechloroisochromophilone III (3), dechloroisochromophilone IV (4), and 6-((3E,5E)-5,7-dimethyl-2-methylenenona-3,5-dienyl)-2,4-dihydroxy-3-methylbenzaldehyde (5)), pencolide (7), and two new meroterpenes (atlantinones A and B (9 and 10, respectively)). While pencolide was detected in the exudates of both control and 5-azacytidine-treated cultures, all of the other natural products were found exclusively in the guttates of the epigenetically modified fungus. All of the metabolites from the P. citreonigrum guttate were tested for antimicrobial activity in a disk diffusion assay. Both sclerotiorin and sclerotioramine caused modest inhibition of Staphylococcus epidermidis growth; however, only sclerotioramine was active against a panel of Candida strains.Our research group has been actively pursuing the development of chemical epigenetic methods for procuring secondary metabolites from fungi. 1 We have demonstrated that this is an effective technique for promoting the transcription of silent biosynthetic pathways involved in the formation of polyketide, non-ribosomal peptide, and hybrid polyketide-non-ribosomalpeptide natural products. 2 Moreover, we have shown that a chemical epigenetics approach is well suited for the generation of structurally unique secondary metabolites with promising drug discovery applications. 3,4 In order to maximize the opportunity for detecting novel secondary metabolites, we have begun using chemical epigenetic induction as a routine part of our screening program involving the exploration of fungi obtained from minimally explored environments/ecological niches (e.g., insects and littoral zones4).* To whom correspondence should be addressed. Tel: (405) 325-6969. rhcichewicz@ou.edu.. † Natural Products Discovery Group, Department of Chemistry and Biochemistry. ‡ Current address: Empresa Brasileira de Pesquisa Agropecuária-EMBRAPA, Coastal Tablelands, Av. Beira Mar, 3250, 49025-040, Aracaju, SE, Brazil. § Department of Chemistry and Biochemistry. ⊥ Ecology and Evolutionary Biology Program.Supporting Information Available: NMR ( 1 H and 13 C NMR, HSQC, HMBC, COSY, and ROESY) data for compounds 6, 7, 9, and 10 and 1 H NMR and 1D difference NOE data for 8 are provided. This information is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2011 May 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOur investiga...

Structures and biological activities of azaphilones produced by Penicillium sp. KCB11A109 from a ginseng field

“…Compound 5 possessed the same absolute configurations at C-7 and C-8 with the known azaphilone, whereas 2 was found to have a different configuration at C-7, and this further suggests the stereochemical diversity of members of the azaphilone family. Four known azaphilones were also isolated and determined as sclerotioramine (9) (Wang et al, 2010), isochromophilone VI (10) (Arai et al, 1995), sclerotiorin (11) (Steyn and Vleggaar, 1976), and 2,4-dihydroxy-6-(5,7-dimethyl-2-oxo-trans-3-trans-5-nonadienyl)-3-methylbenzaldehyde (12) (Matsuzaki et al, 1998) by comparisons of molecular weights, NMR data, and physicochemical properties, such as CD effects and optical rotations, with literature values.…”

Eremophilane Sesquiterpenes from a Deep Marine-Derived Fungus, Aspergillus sp. SCSIOW2, Cultivated in the Presence of Epigenetic Modifying Agents

“…Epigenetic modifying agents, primarily histone-modifying and DNA methylation-modifying agents, have been introduced as promising tools for manipulating the silent fungal genes for the purpose of discovering novel structures [4][5][6]. This approach has already been successfully applied to several marine-derived fungi to discover novel natural products using chemical epigenetic modifying agents, such as the histone deacetylase inhibitors suberohydroxamic acid (SBHA) [7,8] and sodium butyrate [9] and the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) [10,11]. Moreover, studies on the effect of the concomitant addition of an HDAC inhibitor and a DNA methyltransferase inhibitor on fungal secondary metabolite production have been conducted.…”

Chapter 10. Epigenetic Approaches to Natural Product Synthesis in Fungi

“…60 In attempts to isolate novel compounds from 5-AC treated cultures, analysis of treated cultures of Cladosporium cladosporoides by NMR and MS identified novel production of several oxylipins, including (9Z,12Z-)11-hydroxyoctadeca-9,12-dienoic acid, its methyl ester, and a glycerol conjugate. 121 Similarly, treatment of Penicillium citreonigrum yielded six azaphilones, pencolide, and two new meroterpenes 129 (Figures 10.5A and 10.5B). Diatrype species treated with 5-AC resulted in the identification of lunalides A and B.…”