PhD Opportunities

A number of immediate opportunities for the appointment of excellent students with a passion for natural product research and or enzymology and biocatalysis to study toward a PhD within the Goss group exist.

Successful candidates will have an excellent background in organic chemistry, molecular biology, or biochemistry as exemplified by previous high standard project work and a first class or upper second degree at masters level.

For informal enquiries please contact Dr Rebecca Goss at rjmg@st-andrews.ac.uk

 

Projects include:

New Antibiotics Accessed Through Understanding and Harnessing Multifunctional Enzymes for Biocatalysis

Summary: There is an urgent quest for new antibiotics.  During the past 3 decades over 70% of antimicrobials and over 60% of antitumour agents entering clinical trials have been based on natural products, compounds produced by plants and microorganisms. Whilst such compounds provide an excellent starting point for drug discovery, it is often essential to generate analogues with improved physicochemical properties, or to enable further mechanistic studies. Total synthesis of complex natural products can be lengthy and is not always amenable to analogue generation. Series of analogues may be accessed expeditiously through the use of a synergic combination of synthetic biology and organic synthesis.

This project will utilise combined approaches of micro-molecular biology and organic synthesis to probe the natural assembly of a potent antibiotic from a marine organism. Based on an understanding of the biosynthesis, synthetic organic chemistry will be combined with synthetic biology and multi-enzyme biocatalysis to access analogues of a new antibiotic, highly potent against VRSE and MSRA, in order to gain insight into its molecular mode of action, thereby enabling the design and generation of new and improved series of this antibiotic. More information can be found here and here.

 

Genochemetics: Pioneering New Approaches to Accessing Series of New to Nature Natural Products

Summary: A new concept in natural product analogue synthesis:

We are challenging the misperception that natural products are “un med chemable” by pioneering a new and unconventional approach to natural product analogue generation that goes significantly beyond state of the art. Chemically labile motifs within natural products can cause a problem for the synthetic chemist and lead to side reactions. Significant effort is employed to protect sensitive functionality or to avoid introducing this into the natural product until the final stage in the synthesis. Conversely, using synthetic biology to harness biosynthetic processes we will engineer chemically orthogonal and reactive functionality into natural products (the antithesis of protecting groups). Rather than employing a long chemical synthesis of a modified natural product core, the selectively activated core will be made by introducing foreign genes into the natural product generating microorganism to act in concert with the existing biosynthetic machinery. Expression of the foreign gene will result in the introduction of a reactive chemical handle into a selected site within the natural product. This reactive functional handle may then be subjected to a large portfolio of reactions enabling its selective modification.

i)  Genetically installable handles. We are focusing predominantly on three chemically orthogonal handles and their genetic installation into natural products – halogens, epoxides and alkynes. We will develop tools to enable the introduction of these handles into a variety of medicinally significant natural products.

ii) Synthetic functionalisation of handles.Mild conditions for the modification of these handles will be developed, with our aim being, wherever possible, to facilitate the functionalization of the halo and alkynyl natural product without need for its prior purification. We will also explore the potential to genetically install handles that will allow gentle synthetic derivitisation in aqueous media and ideally in the presence of living tissue.

 

Engineered E. coli Biofilms: A Plug and Play System for Biocatalysis in Flow
Summary: This interdisciplinary research, in collaboration with Professor Mark Simmons, Chemical Engineering, University of Birmingham presents a novel methodology for the development and exploitation of engineered biofilm catalysts (EBC) for biotransformations relevant to the fine chemicals and pharmaceutical industries. The investigators’ combination of skills in Chemical Engineering, Chemistry and Microbiology has led to a novel methodology for generating and imobilising EBC on a surface.  This research exploits the natural ability of biofilms to withstand extremes in pH, temperature and mechanical stress, thereby conferring stability to the enzymes immobilized within, making them amenable for use in flow. Specifically it is our aim to determine factors governing stability, microstructure and catalytic activity within the EBC and to enable industrially relevant new biocatalysts to be designed.

Keywords: Natural Products, Biocatalysis, Antibiotics, Anticancer Agents, Organic Synthesis, Micro-Molecular Biology, Synthetic Biology, Biosynthesis, Biosynthetic Elucidation, Genochemetics