In reviewing a selection of recent case studies from our laboratory, we revealed some lessons learned and benefits accrued from the application of mass spectrometry (MS/MS) molecular networking in ...the field of marine sponge natural products. Molecular networking proved pivotal to our discovery of many new natural products and even new classes of natural product, some of which were opaque to alternate dereplication and prioritization strategies. Case studies included the discovery of: (i) trachycladindoles, an exceptionally rare class of bioactive indole alkaloid previously only known from a single southern Australia sample of
; (ii) dysidealactams, an unprecedented class of sesquiterpene glycinyl-lactam and glycinyl-imide from a
sp., a sponge genera often discounted as having been exhaustively studied; (iii) cacolides, an unprecedented family of sesterterpene α-methyl-γ-hydroxybutenolides from a
sp., all too easily mischaracterized and deprioritized during dereplication as a well-known class of sponge sesterterpene tetronic acids; and (iv) thorectandrins, a new class of indole alkaloid which revealed unexpected insights into the chemical and biological properties of the aplysinopsins, one of the earliest and more extensively reported class of sponge natural products.
Co-cultivation of Chaunopycnis sp. (CMB-MF028) and Trichoderma hamatum (CMB-MF030), fungal strains co-isolated from the inner tissue of an intertidal rock platform mollusc (Siphonaria sp), resulted ...in transcriptional activation of a rare class of 2-alkenyl-tetrahydropyran, chaunopyran A (7), and biotransformation and deactivation of the antifungal pyridoxatin (1), to methyl-pyridoxatin (8). This study illustrates the complexity of offensive and counter-offensive molecular defenses encountered during fungal co-cultivation, and the opportunities for activating new, otherwise transcriptionally silent secondary metabolites.
This study showcases the application of an integrated workflow of molecular networking chemical profiling (GNPS), together with miniaturized microbioreactor cultivation profiling (MATRIX) to ...successfully detect, dereplicate, prioritize, optimize the production, isolate, characterize, and identify a diverse selection of new chemically labile natural products from the Queensland sheep pasture soil-derived fungus
sp. CMB-MRF324. More specifically, we report the new tryptamine enamino tripeptide aspergillamides E-F (
-
), dihydroquinoline-2-one aflaquinolones H-I (
-
), and prenylated phenylbutyrolactone aspulvinone Y (
), along with an array of known co-metabolites, including asterriquinones SU5228 (
) and CT5 (
), terrecyclic acid A (
), and aspulvinones N-CR (
), B (
), D (
), and H (
). Structure elucidation was achieved by a combination of detailed spectroscopic and chemical analysis, biosynthetic considerations, and in the case of
an X-ray crystallographic analysis.
An integrated program of chemical profiling (GNPS) coupled with an expanded format 24-well-plate miniaturized cultivation profiling (MATRIX) utilizing traditional as well as grain/pulse and cereal ...media permitted rapid prioritization of Aspergillus terreus CMB-SWF012 as a source of unprecedented natural products. Scaled-up cultivation on rice and PDA yielded the rare tripeptides asterripeptides A–C (1–3), new indolo-sesquiterpene Michael adducts terreusides A and B (4 and 5), and known precursors asterresin A (6) and (+)-giluterrin (7). Structures for 1–7 were assigned by detailed spectroscopic and chemical analysis and biosynthetic considerations.
Molecular network analysis of Streptomyces sp. CMB-MW079 detected rare phosphorylated natural products. Miniaturized cultivation profiling (MATRIX) established optimal conditions for the production, ...isolation, and identification of the polyketide δ-lactone phoslactomycin E (1) and new ester homologues, phoslactomycins J and K (2 and 3), as well as unprecedented heterocyclic analogues, the tetrahydrofuran cyclolactomycins A–D (4–7) and γ-lactone isocyclolactomycins A–C (8–10). We propose a biogenetic relationship linking these cometabolites with the known lactomycins A–C which were tentatively identified as minor cometabolites.
A brown rice cultivation of Aspergillus sp. CMB-MRF324 yielded six new meroterpenes, millmerranones A–F (1–6), and four known analogues, terreulactones A–D (7–10). Millmerranone A (1) possesses a ...unique carbon skeleton bearing a rare cyclic carbonate and undergoes an unprecedented base mediated rearrangement to seco-millmerranone A (1a). We also report on an unexpected base rearrangement of 7 to 7a/b; a plausible biosynthetic relationship linking 1, 7, and 9; and acetylcholinesterase inhibitory properties (IC50 37 nM to >30 μM).
Glutamate-gated chloride channel receptors (GluClRs) mediate inhibitory neurotransmission at invertebrate synapses and are primary targets of parasites that impact drastically on agriculture and ...human health. Ivermectin (IVM) is a broad-spectrum pesticide that binds and potentiates GluClR activity. Resistance to IVM is a major economic and health concern, but the molecular and synaptic mechanisms of resistance are ill-defined. Here we focus on GluClRs of the agricultural endoparasite, Haemonchus contortus. We demonstrate that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times. We further demonstrate that IVM greatly enhances the active durations of single receptors. These effects are greatly attenuated when endogenous IVM-insensitive subunits are incorporated into GluClRs, suggesting a mechanism of IVM resistance that does not affect glutamate sensitivity. We discovered functional groups of IVM that contribute to tuning its potency at different isoforms and show that the dominant mode of access of IVM is via the cell membrane to the receptor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Methods in Microbial Biodiscovery Salim, Angela A; Khalil, Zeinab G; Elbanna, Ahmed H ...
Marine drugs,
09/2021, Letnik:
19, Številka:
9
Journal Article
Recenzirano
Odprti dostop
This review presents an account of the microbial biodiscovery methodology developed and applied in our laboratory at The University of Queensland, Institute for Molecular Bioscience, with examples ...drawn from our experiences studying natural products produced by Australian marine-derived (and terrestrial) fungi and bacteria.
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•Synthesis of echinosulfone A.•Structure revision of the marine natural product echinosulfone A.•Structure revision of the marine natural product echinosulfonic acids A–D.
A short ...Friedel-Crafts mediated total synthesis has informed structure revision of the rare marine sponge natural product echinosulfone A (1a) and the biosynthetically related echinosulfonic acids A–D (2a–5a).
Cultivation profiling followed by chemical analysis of Streptomyces lincolnensis yielded four new isomeric bianthracenes, lincolnenins A–D (1–4), with relative stereostructures assigned on the basis ...of detailed spectroscopic analysis. Lincolnenins A (1) and B (2) exhibit restricted rotation about alternate bianthracene 9–9′ and 9–8′ bridges, respectively, and exist as single atropisomers, whereas C (3) and D (4) are thermally interconvertible atropisomers sharing a common 8–8′ bianthracene bridge. Absolute configurations were assigned to 1–4 on the basis of diagnostic ROESY correlations and ECD calculations, whereas acid-mediated dehydration of 1 led to formation and revision of the absolute configuration of the biosynthetically related known Streptomyces antibiotic, setomimycin (5). Lincolnenin A (1) exhibited significant bactericidal activity against multiple susceptible and drug-resistant Gram-positive pathogens (MIC99 < 2.0 μM), including Mycobacterium tuberculosis H37Ra (MIC99 = 0.9 μM).
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