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Structural Biology of Signalling Proteins In the Bacterial Predator Bdellovibrio

Principal Supervisor: Dr Andrew L Lovering, School of Biosciences

Co-supervisor: Dr Tim Knowles, School of Biosciences

PhD project title: Structural Biology of Signalling Proteins In the Bacterial Predator Bdellovibrio

University of Registration: University of Birmingham

Project outline:

Bdellovibrio bacteriovorus bacteria are natural inhabitants of soil & water and are also found in the oral & faecal flora of animals & man – they are predatory towards other bacteria (including many pathogens, antibiotic-resistant strains) and possess a remarkable lifecycle where they invade the periplasmic space of their prey. Essentially, the larger bacterial prey is eaten from within. An overview of this process is described here: https://www.youtube.com/watch?v=hjMMGCQtkWg.

There is huge potential for using Bdellovibrio in a therapeutic context (Reardon 2015); recent proof-of-principle experiments demonstrating that Bdellovibrio could be used to reduce pathogenic bacterial load in a zebrafish model of infection (Willis 2017).

We are using X-ray crystallography and related methods to uncover the mechanisms by which Bdellovibrio proteins manipulate and metabolize prey bacteria (e.g. Lovering et al 2011, Lerner et al 2012, Lambert et al 2015). This project will look at a specific subset of these predatory proteins (those possessing domains predicted to be involved in signalling, essential in a bacterium with such a staged lifecycle) and use information derived from high resolution protein structures to describe the regulation of predation at the molecular level. This structural biology approach is particularly powerful in the study of this unusual bacterium, as homology to other organisms is weak (predators are uniquely adapted to their unusual lifestyle, wherein a proportion of their genome reflects this extreme specialization). By understanding how predation is controlled/regulated, we will be able to manipulate these processes and learn more the toolkit that is deployed when prey is invaded and killed.

References:

  • Lambert C, Cadby IT, Till R, Bui NK, Lerner TR, Hughes WS, Lee DJ, Alderwick LJ, Vollmer W, Sockett ER, Lovering AL. Ankyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus. Nature Commun. 2015 Dec 2;6:8884
  • Lerner TR, Lovering AL, Bui NK, Uchida K, Aizawa S-I, Vollmer W, Sockett RE. Specialized peptidoglycan hydrolases sculpt the intra-bacterial niche of predatory Bdellovibrio and increase population fitness. PLoS Pathogens. 2012; 8(2):Feb 9 e10025424
  • Lovering AL, Capeness MJ, Lambert C, Hobley L, Sockett RE. The Structure of an unconventional HD-GYP Protein from Bdellovibrio Reveals the Roles of Conserved Residues in This Class of Cyclic-di-GMP Phosphodiesterases. mBio. 2011 Oct 11;2(5)
  • Reardon 2015. http://www.nature.com/news/antibiotic-alternatives-rev-up-bacterial-arms-race-1.17621
  • Willis AR, Moore C, Mazon-Moya M, Krokowski S, Lambert C, Till R, Mostowy S, Sockett RE. Injections of Predatory Bacteria Work Alongside Host Immune Cells to Treat Shigella Infection in Zebrafish Larvae. Curr Biol. 2016 Dec 19;26(24):3343-3351.

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Techniques that will be undertaken during the project:

  • Molecular Biology (chiefly cloning, mutagenesis)
  • Protein expression & purification
  • Protein crystallization
  • Structure Determination
  • X-Ray Crystallography
  • Protein function/analysis
  • Enzyme Assays
  • Biophysical methods (AUC, SAXS, ITC, microscale thermophoresis)
  • Bioinformatics

Contact: Dr. Andrew L Lovering, School of Biosciences