Investigating the diversity of secondary metabolites from filamentous fungi

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Noemi D. Paguigan (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Nicholas Oberlies

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.

Additional Information

Language: English
Date: 2017
Dereplication, Fluorination, Freshwater, Fungi, North Carolina, Quorum sensing
Fungal metabolites
Freshwater fungi
Quorum sensing (Microbiology)

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