(BBSRC DTP) Improving antimicrobial drug discovery and production by deep-engineering of an actinobacterial universal synthetic host

Antimicrobial resistance is an urgent problem that needs to be tackled by discovering new antimicrobial drugs. Genome sequencing has shown that microbial genomes encode the capability to produce an enormous variety of different chemical compounds, including thousands of potential antimicrobials. However, only a tiny fraction of these is currently being clinically used and the vast majority remains uncharacterised. A major bottleneck is the fact that the genetic machinery for compound production tends to be inactive under normal conditions – discovering and characterising antimicrobial leads usually requires their transfer to a heterologous host species. However, typical host candidates are limited in their ability to produce novel chemicals using the transferred genetic machinery from unrelated organisms.  

In this project we will overcome this barrier using the powers of deep genome engineering. We will explore the common design features of the genomes of a particularly talented group of antimicrobial producers, in the class Actinobacteria, which have evolved a highly flexible metabolism pre-adapted to the production of high levels of a wide variety of compounds using horizontally acquired biosynthetic machinery. The student will use comparative genomics and the supervisor team’s insights from earlier attempts to engineer antimicrobial production strains to design a universal antibacterial host genome, which will be synthesised using an innovative combination of de-novo and template-based strategies and validated using the production of selected antimicrobial drug candidates.  

Creating an actinobacterial-derived universal synthetic host genome, which can produce a broad range of new chemicals compounds in a flexible, modular plug-and-play manner, is a long-term ambition, which would greatly expand our ability to access the antimicrobial treasures revealed by genome sequences and facilitate the subsequent steps of compound modification and diversification using combinatorial approaches to create libraries of biosynthetic pathway variants. This project will contribute essential conceptual and technical building blocks towards achieving this ambitious aim.  

https://www.research.manchester.ac.uk/portal/rainer.breitling.html 

https://www.research.manchester.ac.uk/portal/eriko.takano.html 

http://synbiochem.co.uk/ 

Eligibility

Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology. 

Before you Apply

Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How To Apply

To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/