Resource type
Thesis type
(Thesis) Ph.D.
Date created
2024-08-27
Authors/Contributors
Author (aut): Recchia, Michael Joseph John
Abstract
Recent advancements in high-throughput (HT) multi-omics have significantly impacted drug discovery, enhancing the exploration of novel chemistries through innovative analytical techniques. Metabolomics, a fundamental branch within the 'Omics' disciplines, focuses on the comprehensive and quantitative characterization of complex mixtures, often using mass spectrometry (MS) for analysis. Despite progress in multi-omics technologies, the chemical analysis of natural products (NP) mixtures remains a rate-limiting step in the discovery pipeline, creating a gap between chemical and biological profiling. Liquid chromatography (LC) is essential for high-quality chemical analysis of NP mixtures but can be time consuming for large sample libraries. Addressing the limitation, a dual-grid orthogonal sample pooling strategy called MultiplexMS was developed to increase LC-MS throughput. In a proof-of-concept study involving 925 fractionated NP extracts, MultiplexMS demonstrated efficacy by rediscovering all previously reported bioactive metabolites in only 5% of the original MS time. MultiplexMS-Q, an addition to MultiplexMS, introduces mathematical formulations to calculate relative quantitation data from MS features detected in pooled samples. This quantitative information enriches the qualitative data provided by MultiplexMS, offering a comprehensive view of NP mixtures. Advanced MS instrumentation can address sensitivity and mass accuracy limitations associated with chemically profiling complex mixtures. A subsequent study evaluated the benefits of high-resolution (HR) mass spectrometers, emphasizing improved resolving power, scanning speed, and sensitivity while maintaining accurate identification in complex samples. Integrating various omics techniques is crucial for modern NP discovery. Using a combination of metabolomics and genomics, new molecules with unique chemical scaffolds were discovered from underexpressed biosynthetic machinery. These interdisciplinary approaches deepen our understanding of NP chemistry and accelerate drug discovery. MultiplexMS and MultiplexMS-Q represent advancements in HT chemical analysis, bridging the gap between biological and chemical profiling. The continued integration of omics data is essential for discovering novel compounds with potential therapeutic applications. These advancements empower researchers to efficiently uncover new bioactive molecules, contributing to developing new therapeutics.
Document
Extent
181 pages.
Identifier
etd23290
Copyright statement
Copyright is held by the author(s).
Supervisor or Senior Supervisor
Thesis advisor (ths): Linington, Roger
Language
English
Member of collection
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