Browsing by Author "Gray, Christopher A."
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Item Antimycobacterial 1,4-napthoquinone natural products from Moneses uniflora(Elsevier, 2018-10) Li, Haoxin; Bos, Allyson; Jean, Stéphanie; Webster, Duncan; Robichaud, Gilles A.; Johnson, John A.; Gray, Christopher A.A new 1,4-naphthoquinone derivative, 5,8-dihydro-3-hydroxychimaphilin (4) and five known compounds (1, 2 and 5–7) were isolated from an extract of the Canadian medicinal plant Moneses uniflora that significantly inhibited the growth of Mycobacterium tuberculosis H37Ra. The structure of 4 was established through analysis of NMR and MS data and the absolute configuration of the glycone of 5 was determined by chemical transformation and comparison with standards prepared from D- and L-glucose. All compounds isolated were screened against Mycobacterium tuberculosis (H37Ra) and the mammalian HEK 293 cell line and, with the exception of compounds 5 and 7, exhibited marked selectivity in their bioactivity: Compound 1 exhibited potent antimycobacterial activity (IC50 of 5.4 μM) and moderate cytotoxicity (IC50 of 30 μM); compounds 2, 4 and 6 showed moderate antimycobacterial activity (IC50 values from 28 – 47 μM) without affecting the viability of mammalian cells; compound 5 displayed moderate activity in both assays (IC50 values of 44 and 55 μM respectively); and compound 7 was not active in either assay. These data suggest that the Moneses napthaquinone derivatives elicit biological responses in mycobacterial and mammalian cells through disparate modes of action that warrant further investigationItem Caryophyllene sesquiterpenes from a Chaetomium globosum endophyte of the Canadian Medicinal plant Empetrum nigrum(American Chemical Society, 2023-06-02) Morehouse, Nicholas J.; Clark, Trevor N.; Kerr, Russell G.; Johnson, John A.; Gray, Christopher A.Punctaporonins T (1) and U (2), new caryophyllene sesquiterpenes, were isolated with three known punctaporonins, A (3), B (4), and C (5), from the endophytic fungus Chaetomium globosum (TC2-041). The structures and relative configurations of punctaporonins T and U were elucidated based on a combination of HRESIMS, 1D/2D NMR spectroscopic analysis, and X-ray diffraction analysis whilst their absolute configuration is presumed to be consistent with the co-isolated 3–5 on biogenetic arguments. Compound 1 showed weak inhibitory activity against both Mycobacterium tuberculosis and Staphylococcus aureus.Item Culture-dependency of fungal-endophyte isolation and implications for natural products research(University of New Brunswick, 2022-03) Davis, Bradley Rice; Gray, Christopher A.The assemblage of fungi isolated from plant tissues is dependent on the isolation conditions and cannot be assumed to represent the entire endophytic community. A comparison of the two media most used for endophyte isolation [2.0% malt extract (MEA), and 2.4% potato dextrose (PDA)] using three plants (Pyrola elliptica, Pinus strobus, and Sarracenia purpurea) consistently showed that PDA had a higher isolation frequency of endophytic fungi, and a greater number of morphologically distinct fungi recovered per sampling unit. Estimations of the total number of distinct fungi isolable using PDA also exceeded those for MEA. Culture-independent methods of detecting endophytic fungi were assessed for S. purpurea and revealed an additional fungal species, Penicillium spinulosum, that had not been isolated on PDA or MEA. Extracts of the isolated fungi were evaluated in antimicrobial assays where there was no difference in the proportion of active extracts observed between the two isolation media used.Item Discovery of an isothiazolinone-containing antitubercular natural product Levesquamide(American Chemical Society, 2020-05-04) Liang, Libang; Haltli, Bradley; Marchbank, Douglas H.; Fischer, Maike; Kirby, Christopher W.; Correa, Hebelin; Clark, Trevor N.; Gray, Christopher A.; Kerr, Russell G.Antitubercular agent levesquamide is a new polyketide-nonribosomal peptide (PK-NRP) hybrid marine natural product isolated from Streptomyces sp. RKND-216. The structure contains a rare isothiazolinone moiety which has only been reported in collismycin SN. Structure elucidation by NMR spectroscopy was a significant challenge due to a deficiency of protons in this aromatic moiety. Therefore, the genome of Streptomyces sp. RKND-216 was sequenced to identify the levesquamide biosynthetic gene cluster (BGC). Analysis of the BGC provided structural insights and guided stable-isotope labeling experiments, which led to the assignment of the fused pyridine-isothiazolinone moiety. The BGC and the labeling experiments provide further insights into the biosynthetic origin of isothiazolinones. Levesquamide exhibited antimicrobial activity in the microplate alamarBlue assay (MABA) and low oxygen recovery assay (LORA) against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) values of 9.65 and 22.28 µM, respectively. Similar activity was exhibited against rifampicin- and isoniazid-resistant M. tuberculosis strains with MIC values of 9.46 and 9.90 µM, respectively. This result suggests levesquamide has a different mode of action against M. tuberculosiscompared to the two first-line antitubercular drugs rifampicin and isoniazid. Furthermore, levesquamide shows no cytotoxicity against the Vero cell line, suggesting it may have a useful therapeutic window.Item Discovery of natural products from marine derived fungi and endophytic fungi(University of New Brunswick, 2023-10) Morehouse, Nicholas J.; Gray, Christopher A.Natural products are an abundant source of bioactive, complex, and diverse chemical structures. This thesis describes the isolation and structure elucidation of natural products biosynthesized by marine-derived fungi and endophytic fungi with the primary objective of the research being the discovery of new chemical structures. The thesis is divided into two parts: the discovery of new natural products and the development of a new dereplication platform. Three fungal isolates were investigated to discover new natural products. First, investigation of a Penicillium sp. fungus isolated from sea foam resulted in the discovery of a new phenalenone derivative that selectively inhibits the growth of Staphylococcus aureus and Mycobacterium tuberculosis. Second, investigation of an Aureobasidium pullulans fungus isolated from needles of Thuja occidentalis (white cedar), led to the isolation of two new C11-polyketides that inhibit the growth of Mycobacterium tuberculosis. Finally, investigation of a Tolypocladium sp. fungus isolated from the marine macroalga Spongomorpha arcta led to the isolation of two new lipopeptaibols that inhibit the growth of Gram-positive bacteria and mycobacteria. Although these five natural products are new, they are structural derivatives of previously discovered molecules rather than being structurally novel. To improve the likelihood of discovering novel natural products in the future, Structural similarity Network Annotation Platform for Mass Spectrometry (SNAP-MS) was developed. SNAP-MS utilizes molecular networking topology and structural similarity fingerprinting to generate annotations of natural product compound families to aid in the dereplication process. This platform addresses limitations of many currently existing tools, such as the lack of publicly available reference data for most natural products and provides a new tool for analyzing complex mass spectrometry experiments that will improve dereplication capabilities and improve the likelihood of discovering novel natural products.Item Isolation of an antimicrobial racemic phenalenone derivative from a marine-derived Penicillium sp. fungus(Canadian Science Publishing, 2023-10-30) Morehouse, Nicholas J.; Graham, Kelsie M.; Cox, Samantha L.; Johnson, John A.; Gray, Christopher A.A new phenalenone derivative, 2,4,6,9-tetrahydroxy-7-methyl-2-prenyl-1H-phenalene 1,3(2H)-dione (1), was isolated from the ethyl acetate extract of a marine derived Penicillium sp. fungus that exhibited a unique antimicrobial activity profile. The planar structure of 1 was determined through a combination of 1D and 2D NMR experiments, and circular dichroism and polarimetry indicated that it was isolated as a racemic mixture of enantiomers. The antimicrobial activity of 1 was assessed against a panel of Gram-positive and Gram-negative bacteria and fungal strains and it was found to selectively inhibit the growth of Staphylococcus aureus and Mycobacterium tuberculosis. Keywords: Phenalenone, Penicillium, Natural product, AntimicrobialItem Tolypocaibols: Antibacterial lipopeptaibols from a Tolypocladium sp. endophyte of the marine macroalga Spongomorpha arcta(American Chemical Society, 2023-06-14) Morehouse, Nicholas J.; Flewelling, Andrew J.; Liu, Dennis Y.; Cavanagh, Hannah; Linington, Roger G.; Johnson, John A.; Gray, Christopher A.Two new lipopeptaibols, tolypocaibols A (1) and B (2), and the mixed NRPS-polyketide shikimate natural product maximiscin [(P/M)-3)] were isolated from a Tolypocladium sp. fungal endophyte of the marine alga Spongomorpha arcta. Analysis of NMR and mass spectrometry data revealed the amino acid sequences of the lipopeptaibols, which both comprise 11 residues with a valinol C-terminus and a decanoyl acyl chain at the N-terminus. The configuration of the amino acids was determined by Marfey’s analysis. Tolypocaibols A (1) and B (2) showed moderate, selective inhibition against Gram-positive and acid-fast strains, while maximiscin [(P/M)-3)] showed moderate, broad-spectrum inhibition.