Transferring Fungi to a Deuterium-Enriched Medium Results in Assorted, Conditional Changes in Secondary Metabolite Production

Abstract

Deuterium is one of the few stable isotopes that have the capacity to significantly alter a compound's chemical and biological properties. The addition of a single neutron to a protium atom results in the near doubling of its mass, which gives rise to deuterium's characteristic isotope effects. Since the incorporation of deuterium into organic substrates is known to alter enzyme/protein-substrate interactions, we tested the extent to which deuterium enrichment would modify fungal secondary metabolite production. Several fungal cultures were tested, and in all cases their secondary metabolomes were marked by changes in natural product production. Workup of one Aspergillus sp. grown under deuterium-enrichment conditions resulted in the production of several secondary metabolites not previously detected from the fungus. Bioassay testing revealed that in comparison to the inactive crude fungal extract derived from growing the fungus under non-deuterium-enriched conditions, an extract derived from the same isolate cultured in a deuterium-enriched medium inhibited methicillin-resistant Staphylococcus aureus. Using an assortment of NMR and mass spectrometry experiments, we were able to identify the bacterial inhibitor as an isotope-labeled version of pigmentosin A (6). Five additional isotopically labeled metabolites were also obtained from the fungus including brevianamide F (1), stephacidin A (2), notoamide D (3), notoamide L (4), and notoamide C (5). Given the assorted changes observed in the secondary metabolite profiles of this and other fungi grown in deuterium-enriched environments, as well as the fact that 1 and 3-6 had not been previously observed from the Aspergillus sp. isolate used in this study, we propose that deuterium enrichment might offer an effective method for further expanding a fungus's chemical diversity potential.

The inhibitory effects of metabolites from Bacillus pumilus on potato virus Y and the induction of early response genes in Nicotiana tabacum

“…As shown in Fig. 1 , 9 compounds were isolated from the ethyl acetate extract of strain E303035 and identified as cyclo(L-Leu-L-Pro) ( 1 ) (Yue et al 2010 ), cyclo(L-Pro-L-Tyr) ( 2 ) (Li et al 2013 ), Brevianamide F ( 3 ) (Wang et al 2015 ), 2-(3-Indolyl) ethanol ( 4 ) (Böhlendorf et al 1996 ), N-[2-(1H-indol-3-yl) ethyl] acetamide ( 5 ) (Anouhe et al 2015 ), 3, 3-di(1H-indol-3-yl)propane- 1,2-diol ( 6 ) (Zhao et al 2009 ), Lincomycin B ( 7 ) (Argoudelis et al 1965 ), dibutylphthalate ( 8 ) (Dai et al 2006 ), and p -hydroxyphenethyl alcohol ( 9 ) (Lou et al 2001 ).

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Exploring Structural Diversity of Microbe Secondary Metabolites Using OSMAC Strategy: A Literature Review

“…A fungus Aspergillus sp. from Waikiki Beach (Honolulu, HI), generated six isotopically labeled metabolites ( 3 – 8 ) when grown on the deuterium-enriched Czapek broth (Wang et al, 2015a), whereas this strain was found to metabolite a novel prenylated indole alkaloid, waikialoid A ( 9 ) when cultivated in PDB medium. Bioassay results indicated that compound 9 possessed potent inhibitory effect on biofilm formation of Candida albicans with an IC 50 value of 1.4 μM (Wang Q.X.…”

Three New Sesquiterpenoids from the Algal-Derived Fungus Penicillium chermesinum EN-480

“…The organic extract was subjected to vacuum liquid chromatography (VLC) eluting with different solvents of increasing polarity from petroleum ether (PE) to MeOH to yield 9 fractions (Fr. [1][2][3][4][5][6][7][8][9].…”

“…In our previous research, we obtained antimicrobial meroterpenoids from P. chermesinum EN-480 [4], and we recently tried to change the fermentation process to obtain more antibacterial secondary metabolites. As a result, we isolated three new sesquiterpenoids (1-3) as well as four known alkaloids, brevianmide F (4) [8], N-acetyltryptamine (5) [9], cyclo Trp-Ile (6) [10], and cyclo Ile-Pro (7) [11] (Figure 1). Compounds 1-3 were formed by esterification and cyclizing of catenulate farnesyl probably, and this is the first time this type of sesquiterpenoid from natural products has been described.…”