Discovery of Cymopolyphenols A–F From a Marine Mesophotic Zone Aaptos Sponge-Associated Fungus Cymostachys sp. NBUF082

Abstract

Mesophotic coral ecosystems (MCEs) have complex but understudied biodiversity, especially for natural products discovery. Untargeted metabolomics research on 80 extracts prepared from marine sponge-associated fungi, half from shallow reefs (<30 m) and half from MCEs (30–150 m), facilitated prioritization for further study a Cymostachys fungus from a 103 m deep Aaptos sponge. LC-MS target-directed isolation yielded a series of new compounds, cymopolyphenols A−F (1–6), and two known phenylspirodrimanes, F1839-I (7) and stachybotrylactone (8). This is the first report of natural products from the recently described genus, Cymostachys. Compounds 1–6 and 8 contain a dihydroisobenzofuran moiety, and 4–6 are low-order polymers of 1 with novel scaffolds. The structures of the compounds were established by spectroscopic and spectrometric data interpretation, with further support from X-ray crystallography studies of 3 and 4. Compound 3 undergoes facile racemization in solution and was found to crystalize as a racemic mixture. Compound 5 was also obtained in racemic form, and after chiral chromatography, both separated enantiomers racemized in solution by a presumed keto-enol tautomerization. Compounds 1 and 3–6 were found to be weakly antimicrobial (MIC 16–64 μg/ml) in vitro against several Gram-positive and Gram-negative human or aquatic pathogens, compound 5 was shown to chelate iron in vitro at 10 μM, and 8 activated plant disease resistance in vivo in a transgenic model organism.

Targeted Isolation of a Cytotoxic Cyclic Hexadepsipeptide from the Mesophotic Zone Sponge-Associated Fungus Cymostachys sp. NBUF082

“…The isolation and characterization of the fungus Cymostachys sp. NBUF082 researched in this work has been described previously [21].…”

“…In ongoing efforts to discover interesting natural products from fungi in this frontier environment, the Aaptos sponge-associated fungus Cymostachys sp. NBUF082 was previously reported to produce novel low-order polymers of a new aromatic polyol monomer, 7-methoxy-1,3-dihydroisobenzofuran-5-ol, and these have anti-Vibrio activities [21]. Further analysis of extract of this fungus by LC-MS/MS based molecular networking allowed for a targeted strategy to isolate a set of structurally related compounds from other chemical classes.…”

Acremocholone, an Anti‐Vibrio Steroid from the Marine Mesophotic Zone Ciocalypta Sponge‐Associated Fungus Acremonium sp. NBUF150

“…MCEs provide up to 80 % of prospective coral reef ecosystems globally but relatively less research has focused on them compared to shallow reefs [22] . The continuous program devoted to the search for structurally new and bioactive molecules from MCEs, [23] we have remained committed on the natural products chemistry of cultivatable sponge‐associated fungi because they are prolific producers [24] and offer ease in controlling fermentation and genetic manipulation for downstream development. Among them, the fungus Acremonium sp.…”

Cytotoxic Polyketide Metabolites from a Marine Mesophotic Zone Chalinidae Sponge-Associated Fungus Pleosporales sp. NBUF144

“…Among them, cymopolyphenols D-F are low-order polymers of cymopolyphenols A that have novel chemical scaffolds. As a continuation of this work of mining new or novel fungal metabolites from MCEs, a second organism was prioritized from the same strain library after the previously reported molecular network [26] was adapted to highlight the secondary metabolite-producing activity of a Pleosporales sp. NBUF144 fungus, which was derived from a 62 m deep Chalinidae family sponge (Figure S1).…”

“…Several fungi with novel metabolite-producing potential were prioritized for further study after applying the combined strategy of LC-MS/MS molecular networking [24] with the OSMAC (One Strain MAny Compounds) approach [25] of crude extracts from 80 sponge-associated fungi (40 from shallow water and 40 from MCEs;Supplementary Material Figure S1). For example, in the previous work, the organism first prioritized was a Cymostachys fungus that yielded a series of new polyketide compounds, cymopolyphenols A-F [26]. Among them, cymopolyphenols D-F are low-order polymers of cymopolyphenols A that have novel chemical scaffolds.…”