Genome-led discovery of novel microbial compounds

Lead Research Organisation: University of East Anglia
Department Name: Graduate Office

Abstract

Many bacteria have evolved the ability to produce a stunning arsenal of complex secondary metabolites, where the structural complexity of these natural products reflects the exquisite reactivity of the enzymes in natural product pathways. Many of these compounds are clinically useful medicines, but it was assumed that the pipeline of biologically useful compounds produced by bacteria had been exhausted by activity-based screening. Tantalisingly, recent widespread genome sequencing shows that many bacteria have an unrealised potential to produce as many as ten times more compounds than have been identified thus far. These "cryptic" pathways may be transcriptionally silent and need switching on, or their products may have been overlooked traditional analysis methods.

The aim of this project is to characterise pathways that are predicted to be biosynthetically unprecedented, and thus provide a high probability of producing molecules with novel architectures and novel bioactivities. Pathways have been chosen following detailed bioinformatic analyses of bacterial genomes, and will be studied using state-of-the-art techniques that span microbiology, synthetic biology and biochemistry, including pathway expression in host strains, regulatory analysis of target genes, and mass spectrometry-based metabolomics.

Publications

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Russell AH (2018) Doxycycline in UK guidelines for hospital-acquired pneumonia: where is the evidence base? in The Journal of antimicrobial chemotherapy

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011216/1 01/10/2015 30/09/2023
1800125 Studentship BB/M011216/1 01/10/2016 30/09/2020 Alicia Russell
 
Description Our research has led to the discovery of a large and and diverse family of biosynthetic gene clusters in bacterial genomes, which encode for production of currently unknown natural products. Natural products from bacteria are important compounds, as they have historically been a valuble source of medicines such as antibiotics and anticancer drugs.
Although currently unpublished, our research so far has involved cloning and expressing one of these uncharacterised gene clusters, in order to identify the compound produced by this set of genes. A clear pathway product has been identified using this approach, using genetic and metabolomic-based experiments. This compound has now been purified and has been subjected to NMR (nuclear magentic resonance) and bioactivitiy experiments, in order to determine the chemical structure and biological activity of this particular compound. This work can now be applied to investigating further uncharacterised biosynthetic gene clusters, which could encode for important new compounds.
Exploitation Route The knowledge gained so far from the characterised pathway will be used to guide characterisation of further related biosynthetic gene clusters.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description British Science Association stand at Norwich Food & Drink festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact As part of the Norwich food and drink festival, the Norwich branch of the British Science Association held a stall about the Chemistry of taste and smell. The purpose of the event was to engage the general public in science, explain our work as researchers and provide information about the British Science Association. The stand included various information and activities about food and chemistry. I volunteered at this event, which gave me the opportunity to talk to the general public about science in general, and the research I carry out at the John Innes centre. The general public seemed very interested in our stall and the science we talked to them about. The children were particularly fond of our 'tasting' experiments, but the parents were also very interested.
Year(s) Of Engagement Activity 2018
 
Description British Science Association treasure hunt 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The Norwich branch of the British Science Assocaiton organised a science treasure hunt in norwich, with various stalls accross the city demonstrating different areas of science. The purpsose of the event was to get children engaged in science, explain our work as scientists and provide information about the British Science Assocation. I volunteered on the chemistry stall, where we had models of chemical structures that we used to explain how molcules are made up. We also had different pots of herbs and spices with strong smells, which we used to demonstrate how different chemical structures are resposible for different scents. The general public were very interested in our stand, and it was a great platform to explain the work I do as a PhD student.
Year(s) Of Engagement Activity 2017
 
Description JIC50 open day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The John Innes Centre held an open day to celebrate 50 years since moving to Norwich. The purpose of the event was to showcase all of the research carried out at JIC, and to engage the general public with various aspects of science. I helped to volunteer at the molecular microbiology 'antibiotic hunters' stand, which featured work, information and activities about our work on Streptomyces and natural products discovery. We had various agar plates with Streptomyces and bacteria from the soil, to show what the bacteria look like and what can be found in the soil. We also had agar plates containing bacteria and antibiotics showing zones of inhibited growth, to show how antibiotics work and how we can discovery activity of new compounds. These tools were a great way to explain to the general public our work on Streptomyces and natural products discovery. It was also an important platform to explain antimicrobial resistance, the importance of protecting current antibiotics and the urgent need to discovery new antibiotics. The stall also included activities for children, such as searching for 'novel bacteria' (different shaped objects) in different environments such as soil, sand and water. This helped to highlight that can we search for new bacteria in different locations, which could also lead to the discovery of novel antibiotics. The general public seemed very interested and engaged in our work, and the stall sparked lots of questions and discussions about antibiotics. The open day was very popular with hundreds in attendance, so we achieved a wide reach.
Year(s) Of Engagement Activity 2017
 
Description Women of the future event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The John Innes Centre held a 'Women of the future' event, where year 10 girls were invited to learn about science, and to encourage them to persue scientific careers. As part of this I volunteered to present a poster of my work, explaning the general principles of searching for new antibitoics from soil bacteria such as Streptomyces, and the different scientific methods that we use. The girls asked questions about the work, and some of the school teachers also came to have a look and ask questions. The JIC comunications team reported that the event was successful and the girls who attended learnt a lot about the various science carried out by women at the John Innes Centre.
Year(s) Of Engagement Activity 2017