Combatting antibiotic resistance by targeting the sensory networks that control pathogenicity, Biological Sciences - PhD (Funded)

The MRC has awarded the GW4 BioMed DTP additional studentships for an October 2017 start. This project is in competition with 40 that are now being advertised across the DTP.

Project description:

Antibiotic resistance is a major problem in the treatment of bacterial infections. Novel ways of tackling infection are urgently needed. Bacteria rely upon sensory networks to sense threats and to respond accordingly. This project aims to assess the potential of targeting these sensory networks that bacteria depend upon for their survival.

Antibiotic resistance is a major problem in the treatment of bacterial infections. New strategies for tackling infection are urgently needed and a promising way is to target the sensory networks that bacteria use to choreograph their behaviour during infection. Sensory networks employing multiple different sensors (multikinase-networks) allow bacteria to monitor the state of their host and to decide upon the optimal strategy during infection. In these networks, each sensor (kinase) detects a different stimulus, and the signals are integrated allowing the bacteria to weigh-up the different signals and to make the important decisions regarding the progress of the infection. Interfering with these multikinase-networks has great potential to reduce bacterial virulence. However, since some bacteria have hundreds of different sensors, unravelling which sensors work together in these networks is challenging and a major rate limiting step for devising ways of targeting these networks to reduce virulence. We have developed a bioinformatic method that allows rapid prediction of which sensors will assemble into multikinase-networks and this has the potential to greatly speed up the discovery of these promising drug targets. The aim of this project is to characterise a novel network that we have predicted in an important pathogen, Burkholderia pseudomallei, the causative agent of melioidosis. This work will investigate this multikinase-network as a potential drug target, and more widely, by validating our prediction method will streamline the discovery of these promising drug targets in other pathogens. This multikinase-network includes two sensors that we have recently shown are essential for cell growth, suggesting that the network is likely to be an excellent drug target.

Objectives:

1. Verify the prediction that the sensors work together as a multikinase-network by using two-hybrid and phosphorylation assays.
2. Determine why this network is essential for growth by producing conditional mutants and using these to identify the regulon of the network.
3. Identify the stimuli sensed by the kinases using binding assays and structural characterisation of the sensory domains using X-ray crystallography.

Outcomes:

Achieving these objectives will, firstly, characterise a crucial multikinase-network in an important pathogen, secondly, assess its potential as a drug target and thirdly, by validating our prediction method will accelerate identification of these promising drug targets in other pathogens. We will engage with and the DiscoverAssist drug discovery venture run by Stevenage Bioscience Catalyst and the University’s Knowledge Transfer section to exploit the promising drug targets revealed by this project.

Start date: October 2017

Eligibility:

The Doctoral Training Partnership welcomes applications from both UK and EU applicants; however, as a consequence of the EU referendum result, final award decisions will depend on the outcomes of the UK/EU negotiations. If the Research Council (MRC in this instance) withdraws funding for EU students, all EU applicants will be ineligible for entry into the GW4 BioMed MRC DTP.

All EU applicants must have been ordinarily resident in the EU for at least 3 years prior to the start of their proposed programme of study. Due to funding regulations there are fewer studentships available for EU students who have not been resident in the UK for at least 3 years prior to the start of this course. By using a mixture of MRC and University funding all studentships will be fully funded.

How to apply:

The deadline for applications is 8th June at 0930.

Applications will be via an online form and applicants will also be responsible for forwarding an academic transcript and two references to the DTP should they be shortlisted for interview.

Interviews will take place on Friday 30 June.

For an overview of the MRC GW4 BioMed programme, please see website www.gw4biomed.ac.uk

For project related queries, please contact Dr Steven Porter.