Search

"Fungi are pathogenic to plants, humans, and animals, and secondary metabolites produced by fungi are implicated in these interactions. As part of an interdisciplinary project to identify the chemical and genomic differences between pathogenic and non-pathogenic fungi, this research identified the chemical differences among Aspergillus section Fumigati. During the research, eight fungal strains were grown under three different temperatures, and 13 different media types were evaluated for their chemical diversity. Chemical studies resulted in 30 secondary metabolites and a variety of chemometric comparisons. The characterized secondary metabolites were compared between strains using several different methodologies, including chemometrics, dereplication, and biosynthetic gene clusters. These comparisons shed light on how secondary metabolites affect pathogenicity in Aspergillus section Fumigati. Bioinformatic analysis of the genome of Aspergillus fischeri predicted the presence of 48 biosynthetic gene clusters, yet only 5 classes of secondary metabolites were identified by chemical characterization. Interaction-driven secondary metabolite discovery (i.e., co-culturing) was used to activate silent biosynthetic gene clusters. This methodology was utilized successfully by co-culturing A. fischeri and Xylaria flabelliformis, which produces the FDA-approved antifungal drug griseofulvin; to activate secondary metabolites not observed when the two fungi were grown in monoculture. The co-culture resulted in the characterization of a novel scaffold with cytotoxic activity."--Abstract from author supplied metadata.

"Verticillins are a class of dimeric epipolythiodioxopiperazine alkaloids that are known to have IC50 values of 10 nM or less in various human cancer cell lines This biological activity makes them potential candidates in the search of new anticancer drugs. However, further studies are hindered by limited supply when isolating verticillin class secondary metabolites from fungal sources. Thus, the search for fungal strains that produce these secondary metabolites at equal or greater abundances than the fungal strain currently being used in our lab, MSX59553, is necessary. This study revealed MSX59549 as a fungal strain of interest due to its production of verticillin A and verticillin H in higher abundances than MSX59553. Three additional fungal strains, MSX39480, MSX43578 and MSX60138, were also found to produce more verticillin H than MSX59553. These results lead to optimizing the isolation of verticillins for use in future chemical and pharmacological studies. The generation of fluorinated verticillin derivatives has been achieved using precursor directed biosynthesis to incorporate 5-fluorotryptophan into the verticillin structures while retaining the potent biological activity. Further precursor directed biosynthesis experiments using 5-hydroxytryptophan, 5-chlorotryptophan and 5-bromotryptophan lead to the production of 9-hydroxyverticillin A and 9-chloroverticllin A. Further studies involving the isolation of these verticillin derivatives and semisynthetic modification via cross coupling reactions may improve pharmacological properties within the verticillin class."--Abstract from author supplied metadata

"This study was conducted as part of an ongoing collaborative project to investigate the chemical diversity of fungi in search of new anticancer drug leads. Fungi have shown to be prolific producers of dynamic secondary metabolites, which exhibit a vast array of physiological activities. In particular, naphthoquinones and their derivatives have long been of interest to medicinal and natural product researchers due to their diverse biological activities such as cytotoxicity, antibacterial, antifungal, antiparasitic, and insecticidal. An established dereplication protocol for screening and prioritization of fungal samples for cytotoxicity, indicated that the biological activity of MSX53507 was not attributable to any compounds (new or known) previously isolated and identified in our research laboratory. Bioactivity-guided fractionation, the primary methodology in our laboratory in which results can take weeks, was conducted solely for screening and prioritization of fractions for further investigation. Preliminary work yielded compounds which encompass an easily identifiable feature in 1H-NMR spectroscopy that is characteristic to this class of compounds. Employing a proton-NMR guided fractionation methodology for purification of biologically active fractions, led to the isolation of four new naphthoquinone analogues (1, 3, and 6-7), two known compounds (4-5) and a naphthoquinone previously misidentified in the literature (2). Naphthoquinone's broad spectrum of biological activity led us to test compounds 2, 5, and 6 against Staphylococcus aureus (ATCC 35667) and a clinically relevant methicillin-resistant S. aureus strain (MRSA) where 5 was the most active with minimum inhibitory concentrations (MICs) of 2.3 µg/mL and 16.0 µg/mL, respectively."--Abstract from author supplied metadata. [This abstract has been edited to remove characters that will not display in this system. Please see the PDF for the full abstract.]

"Viridicatumtoxin A is a unique tetracycline-like aromatic polyketide first isolated as a mycotoxin from Penicillium viridicatum in 1973. Along with its 5-oxo derivative, viridicatumtoxin B, discovered in 2008 from the liquid fermentation cultures of another Penicillium sp. (strain FR11) has exhibited cytotoxicity against the NCI-H460 human lung carcinoma cell line, KB3-1 human cervix carcinoma cell line, and SW620 human colon carcinoma cell line with reported IC50 values of 1.0 uM, 2.5 uM and 1.0 uM respectively. Based on the scarcity and the more bioactive properties of viridicatumtoxin B, Nicolaou and coworkers in 2013 achieved the total synthesis of viridicatumtoxin B; albeit through a lengthy protocol which would not be scalable. In this context, and as part of our ongoing research centered on the optimization of drug leads for the treatment of cancer, my project is focused on the enhanced production of viridicatumtoxin A from fungal cultures which would provide materials for synthesis of more bioactive analogues."--Abstract from author supplied metadata. [This abstract has been edited to remove characters that will not display in this system. Please see the PDF for the full abstract.]

"Natural products continue to be a fertile source of leads for drug discovery, as a large extent of the world's biodiversity has been untapped for their chemical diversity and biological activity. With the continuing need for new drug leads due to the increasing emergence of drug-resistant pathogens and diseases, this dissertation focused on three key strategies in drug discovery including: use of structure-activity relationship studies starting with a known bioactive pharmacophore; exploration of understudied ecological groups for new chemistry; and development of dereplication strategies. Fungal secondary metabolites are known to possess privileged pharmacophores that can be ideal starting points for semi-synthetic (or synthetic) approaches to explore structure-activity relationship and produce new therapeutic candidates. In this work we examined the effect of fluorine substitution as a strategy to expand the therapeutically-relevant chemical space of isolated fungal secondary metabolites. The chemical space of the isolated and synthesized fungal secondary metabolites were characterized by principal component analysis to correlate the observed bioactivities. Undoubtedly, fungi have an excellent track record in providing chemical entities that can be developed into life-saving therapeutics. Freshwater ascomycetes, an ecologically distinct group of fungi, offer a unique opportunity to discover new chemical diversity, as they are underexplored in comparison to other niches. Chemical investigations of freshwater fungal isolates presented in this dissertation led to the isolation and identification of new secondary metabolites. These studies highlighted the untapped potential of this group of organisms. One of the major challenges of working with natural products is the re-isolation of known compounds. Thus, to circumvent this issue and increase the efficiency of the discovery of new leads, a dereplication methodology using a complementary suite of hyphenated techniques, specifically ultra-performance liquid chromatography-photodiode array-high resolution tandem mass spectrometry for targeted screening of compounds was developed. In conjunction to this, the identified hits were expanded upon by screening for potential analogues using mass defect filtering."--Abstract from author supplied metadata

"Natural products have proven to be a good source of anticancer drugs since the 1940's. In fact, they have influenced the creation of 65% of all 246 anticancer drugs since that time. Fungi in particular provide an almost untapped source of compounds with promising bioactivity. To access compounds from natural products, an extraction and purification process using flash chromatography, and high performance liquid chromatography is needed. Characterization of those compounds is done using high-resolution mass spectrometry and NMR spectroscopy. These methods were used to isolate and characterize six known compounds that were added to an in-house database. Leporin B, leporin C, austdiol and 7-epi-austdiol were all isolated from Scytalidium cuboideum strain 68345. Leporin B has specifically proven to be effective in different aspects of research including, its effect on hexokinase II and it has shown potential as a cytotoxic compound towards cancer cells. The re-isolation of leporin B has increased the in-house supply for use in future experimentation. Through the re-isolation of leporin B, leporin C was found. Leporin C is new to natural product; however, the compound has been previously synthesized, and it only differs from the structure of leporin B by one oxygen atom. Austdiol and 7-epi-austdiol were also isolated during the search for leporin B. Fungal strain MSX74367 was also studied, and yielded, 9-O-methylbostrycoidin and 8-O-methylfusarubin. The benzoisoquinoline structure, the core structure of 9-O-methylbostrycoidin and 8-O-methylfusarubin, is new to the current in-house database of over 300 compounds isolated from fungi. Mass defect analysis and high-resolution mass spectrometry were used in an effort to isolate other benzoisoquinoline type compounds through mass guided fractionation; however, the process was unsuccessful in finding additional analogues. In total, six compounds were found from two different strains of fungi, all of which were new to an in-house database. The fungus Scytalidum cuboideum, in particular, produced leporin B and leporin C, which was isolated for the first time from a natural source."--Abstract from author supplied metadata

"With this study, we explored the potential role of fungal endophytes in the antimicrobial activity of the medicinal plant goldenseal, Hydrastis canadensis L. (Ranunculaceae). A total of 23 fungal cultures were obtained from surface-sterilized samples of H. canadensis roots, leaves and seeds. Eleven secondary metabolites were isolated from these fungal endophytes, five of which had reported antimicrobial activity. Hydrastis canadensis plant material from the same harvest was analyzed for the presence of fungal metabolites using liquid chromatography coupled to high resolving power mass spectrometry. One fungal metabolite, the antimicrobial compound alternariol monomethyl ether, was detected both as a metabolite of the fungal endophyte Alternaria sp. isolated from H. canadensis seeds and as a component of an extract from the H. canadensis seed material. The concentration of this compound (991 ppm in dry seed material) was in a similar range that has previously been reported for metabolites of ecologically important fungal endophytes. The seed extracts themselves, however, possessed no significant antimicrobial activity."--Abstract from author supplied metadata.