Integrating genomic methods with C. elegans phenotypic screening to identify bioactive natural products
File(s)
Author(s)
Evans, Bonnie
Type
Thesis
Abstract
Natural products derived from bacteria have long driven the discovery of drugs and other compounds. Genomic methods and synthetic biology have made it possible to engineer large bacterial libraries that produce diverse natural products in the lab. However, there is a lack of high-throughput approaches to screen these libraries in vivo. Here we show that Caenorhabditis elegans can be used to discover bioactive natural products by feeding them engineered microbes and tracking and quantifying their behaviour. Natural products with strong behavioural effects on C. elegans were identified from the targeted activation of biosynthetic gene clusters in entomopathogenic bacteria. The mechanisms of action behind these behavioural changes were explored. Functional screening of a soil metagenomic library of 11,880 samples was performed for the first time to identify behaviour-modifying clones. Additionally, genetic and chemical strategies to maximise the sensitivity of C. elegans to natural products were evaluated. This work highlights the potential of C. elegans in accelerating the discovery of natural products with significant effects on animal physiology.
Version
Open Access
Date Issued
2025-01-08
Date Awarded
01/09/2025
License URL
Advisor
Brown, Andre
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)