Date of Degree
Access restricted until 07/29/2021
PhD (Doctor of Philosophy)
Gloer, James B
First Committee Member
David F Wiemer
Second Committee Member
Stone, Elizabeth A
Third Committee Member
Forbes, Tori Z
Fourth Committee Member
Quinn, Daniel M
The past several decades have seen a rise in the numbers of fungal infections due to an increase in the population of immune-compromised individuals. Some of the most common types of invasive fungal infections are caused by Candida, Aspergillus, and Cryptococcus species. The current treatments for systemic fungal infections remain unsatisfactory because of resistance and toxicity problems. Because of this, there is a growing need for classes of antifungal agents effective against these pathogens.
Fungi have proven to be an excellent source of novel secondary metabolites possessing a range of bioactivities, including antifungal effects. Most of the research described in this thesis stems from an ecology-based approach for selecting types of fungi for investigation in search of novel bioactive metabolites. Members of three ecological niche groups are discussed: mycoparasitic/fungicolous, endophytic, and coprophilous fungi.
Mycoparasitic or fungicolous fungi are those that colonize other fungi and often cause some level of damage to the host. If damage occurs, it may be caused in part by antifungal natural products. Chemical investigations of nine isolates of fungicolous or mycoparasitic fungi (eight of which displayed antifungal activity) described in this thesis afforded five new compounds and 12 known compounds. Three of these known compounds have been reported to display antifungal properties, however, several others have not been tested in bioactivity assays. Due to this and unexpected loss of access to several of the antifungal assays explored in the initial prioritization process, the source of the original extract activity was not identified.
Endophytic fungi are those that inhabit plant tissue and may or may not cause damage to the host. In some cases, colonization of a plant by fungi may be beneficial to the plant by providing protection against unwanted insect or microbial pests, which may be the result of bioactive compounds being produced by the colonizing fungus. Chemical investigation of 10 isolates of endophytic fungi described herein (five of which produced antifungal extracts) afforded 21 known compounds and four new metabolites. Of these, three extracts contained known antifungal compounds as major components, indicating that they were responsible for the original observed extract activity. In other cases, loss of access to the antifungal assays employed in the initial selection resulted in the source of the extract activity remaining undetermined.
Coprophilous fungi, those that colonize the dung of herbivores, inhabit a nutrient-rich environment populated by many other organisms including other fungi, bacteria, insects, and protists. The production of bioactive compounds by coprophilous fungi might help provide them with a competitive advantage in this environment. Studies of 14 coprophilous fungal isolates (many of which displayed antifungal activity) are described in this thesis, leading to identification of twenty-five known compounds and nine new compounds. The majority of extracts yielded at least one metabolite known to have antifungal activity or one or more new compounds displaying these properties.
In addition to the fungal isolates described in this thesis, six new stilbene-type phytoalexins were isolated from peanut seeds (Arachis hypogaea). These compounds are produced by peanut seeds that had been challenged by a mycotoxin-producing fungal invader and may serve to some degree as chemical defenses.
A variety of separation techniques were utilized to isolate compounds from a range of classes, including terpenoids, polyketides, and peptides. Structures were established mainly based on analysis of various 1D and 2D NMR data aided by mass spectrometry. Relative stereochemical configurations were determined, where feasible, based on coupling constants and NOE experiments, whereas absolute configurations were determined using Mosher’s or chemical degradation methods.
Several new secondary metabolites with distinctive chemical features were isolated, as well as many known compounds, some of which displayed bioactivity in medically or agriculturally relevant assays. The work described here illustrates that these targeted groups of fungi are capable of producing a structurally diverse array of bioactive natural products and supports their selection as targeted sources of potentially useful compounds.
xxii, 280 pages
Includes bibliographical references (pages 268-280).
Copyright © 2019 Nicole Marie Dischler
Dischler, Nicole Marie. "Investigations of targeted natural sources in search of bioactive metabolites." PhD (Doctor of Philosophy) thesis, University of Iowa, 2019.
Available for download on Thursday, July 29, 2021