November 29th, 2013 | Category: Metabolic engineering, Protein design, Synthetic Biology | Leave a comment

Potential PhD Position: Biosynthetic Lego: Building antibiotic assembly lines from first principles

There is a PhD position available with Paul Race at Bristol that I will be co-supervising (subject to securing the funding). If successful this will be funded through the South West Doctoral Training Partnership. The PhD will be a fully-funded, four-year programme designed to provide training in cutting edge world-class bioscience and food security research skills.

The project details are below (and also here), and the deadline for application is Friday 10th January 2014. Coincidentally the last day of the SEB Synthetic Biology workshop (shameless plug): deadline for abstracts and registration looming (Dec 6th)!

Main supervisor: Dr Paul Race (School of Biochemistry, University of Bristol)

Second supervisor: Dr Thomas Howard (I really should get my web-page updated) (Department of Biosciences, University of Exeter)

With: Dr Ross Anderson (School of Biochemistry, University of Bristol) & Prof Chris Willis (School of Chemistry, University of Bristol)

Nature has evolved many elegant strategies for the assembly of complex bioactive natural products. The most sophisticated of these involves the action of giant assembly line like megasynthases, that fuse and tailor simple carboxylic acid monomers into a vast array of elaborate carbon scaffolds. This biosynthetic logic is found extensively in the polyketide pathway, and has provided us with many of our most important clinically used antibiotics, e.g. the tetracyclines. There is considerable interest in the rational reengineering of these enzymatic machines, en route to the production of ‘non-natural’ natural products with enhanced bioactivities. To date reengineering strategies have focused on the deletion, insertion, or transplantation of defined synthase components within or between pathways. These modifications have been predominantly directed by bioinformatic analysis of nucleotide sequences. Using molecular level structural information of megasynthase components to guide synthase reengineering is an inherently more powerful approach for manipulation, as module/domain boundaries, enzyme active sites, protein-protein interaction interfaces and inter-module/domain linkers can be accurately defined and interrogated. Further, by using these data as a starting point one is well placed to begin constructing megasynthases de novo, introducing specified biosynthetic functionality to yield desired chemical and stereochemical output in the final pathway product.

This project will marry the complementary expertise of Race (structural enzymology natural product biosynthesis), Howard (pathway redesign and genome engineering), Anderson (enzyme design) and Willis (analytical and synthetic chemistry), in attempting to construct, from first principals, minimal assembly line like megasynthases for the production of new to science polyketide antibiotics. Our approach will be to use the considerable volume of detailed structural and functional information garnered in the applicants’ laboratories (crystal/NMR structures, enzymatic analyses, PPI studies, chemical information, etc.) to construct minimal synthase mosaics with defined biosynthetic activities. We will explore and define the rules of synthase construction and introduce our new systems into microbial hosts en route to the scaleable production of new chemical entities. All novel compounds isolated from this study will be tested for antimicrobial activity and where appropriate taken forward for clinical evaluation.

During the first year of the project the student will undertake 2 rotation projects. The first of these will be based in the Race lab, University of Bristol and will focus on the design and synthesis of the first iteration ofde novo minimal synthases. During this rotation training will be provided in protein structure analysis and enzymological methods. The second rotation project will be performed in the Howard lab, University of Exeter. During this placement training will be provided in genome engineering, molecular biology and associated analytical methods. Please note, as the second rotation project will be located in Exeter, depending on your preference you will be either required to travel to Exeter on a daily basis or accommodation will be provided at Exeter for yourself.

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