Phd - Acyl Carrier Proteins: The key to successfully engineering new biosynthetic pathways.

A PhD project is available for commencement in September 2017 as one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP). The SWBio DTP is a BBSRC-funded PhD training programme in the biosciences, delivered by a consortium comprising the Universities of Bristol (lead), Bath, Cardiff and Exeter and Rothamsted Research. The SWBio DTP projects are designed to provide outstanding interdisciplinary training in a range of topics in Agriculture & Food Security and world-class Bioscience, underpinned by training in mathematics and complexity science. Each project will be supervised by an interdisciplinary team of academic staff and will follow a structured training 4-year PhD model.

More information on this scheme in general can be found at http://www.bristol.ac.uk/swbio/projects_available/index_html and click on the window entitled Biomolecular and Biophyscial Studies where you will see this project advertised (second on the list). Also this advert, can be found separately on PhD.com at https://www.findaphd.com/search/PhDDetails.aspx?CAID=859 which will provide additional general information. This program offers a tailored PhD experience with research rotations, lectures courses and a placement period within UCB. You will be part of a cohort of up to 15 fellow students and the whole package makes an excellent experience. Appointment is by competitive interview and the closing date for online applications at the above SWBio website is Monday 5th December. 

There is a pressing need for the development of new high potency antibiotics active against multiply resistant and/or emerging bacterial pathogens. Current approaches for antibiotic discovery have proven inadequate in combating the increasing problem of antimicrobial resistance. This is dramatically illustrated by the fact that in >25 years, only one new class of antibiotic has entered clinical use (Daptomycin). Dame Sally Davies, England’s Chief Medical Officer, recently described the rise of antibiotic resistant bacteria as an “apocalyptic threat, as important and deadly as climate change and international terrorism”. Natural products and in particular the polyketides are amongst the preeminent sources of ‘new’ antibiotics, and are being increasingly targeted for clinical development. This PhD project is aimed at furthering fundamental studies of polyketide biosynthesis that underpins the development of clinically viable ‘new-to-nature’ antibiotic agents. Specifically it will focus on key aspects of the complex, multi-component megaenzymes responsible for the biosynthesis of the compounds mupirocin and kalimantacin. The over-arching aim is to answer a number of fundamental questions regarding the processes involved in the assembly of these complex small molecules, and use this information to direct develop ways to reengineer these and other megaenzymes, en route to the production of novel antibiotics.

This interdisciplinary project will combine the expertise of chemists, biochemists, structural biologists, molecular modellers and microbial geneticists to elucidate how key components of these pathways, focusing on the acyl carrier proteins (ACP), can be engineered to guide specific modifications of biosynthetic intermediates and how they can be programmed to perform a new function, thereby opening the possibility of incorporating new chemistry into a natural product at will. For example, in the figure, a circuit analogy is used to illustrate how the ACP acts a logic gate and diverts biosynthetic flux to an external (in trans) protein module which performs a specific chemical modification step, before restarting molecular assembly along the linear ‘in-cis’ pathway. In the example shown below, the result is to incorporate specific β-branches at defined points on the molecule (indicated by simplified coloured circles at the relevant points). One goal is to introduce these steps at positions in an assembly line that do not have them at present. We will also use these systems to answer more general fundamental biosynthetic questions so we can design pathways in a rational way and in turn produce novel high value chemicals including variants of existing pharmaceuticals.

Funding Notes

The studentships will provide funding for a stipend (currently £14,296 per annum for 2016-17), research costs and UK/EU tuition fees at Research Council UK rates for 48 months (4 years) for full-time students, pro-rata for part-time students.

Supervisors: Prof Matthew Crump, Dr Race and Prof Willis