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*EASTBIO* Exploring the role post-translational modification in immunity evasion by Acinetobacter baumannii during infection


School of Biology

About the Project

Acinetobacter baumannii is a Gram-negative bacterium responsible for a large number of hospital-associated bloodstream and lung infections worldwide. Carbapenem-resistant A. baumannii strains are widespread, and the WHO ranked these strains as a top priority against which novel antibiotics must be developed. To slow down the emergence of drug resistance, novel bacterial molecular targets must be explored, as current drug targets already have resistance mechanisms circulating in the bacterial population which are readily acquired by a given pathogen. Therefore, the molecular and structural characterisation potential novel targets in A. baumannii is a necessary step to enable the development of novel antibiotics.

A specific catabolic pathway of A. baumannii has been discovered to function as a virulence factor: the initial metabolite in this pathway is a potent neutrophil chemoattractant. Thus it must be degraded efficiently during infection, otherwise it accumulates, quickly attracting innate immunity cells of the host which attack and kill A. baumannii, clearing the host of infection. Accordingly, knockout of A. baumannii genes encoding enzymes of this pathway renders the bacterium incapable of mounting an infection. Therefore novel drugs that inhibit this pathway would cause the metabolite to accumulate and attract neutrophils, stopping A. baumannii infection in its tracks. Importantly, these enzymes have no homologues in mammals, which bodes well for the design of specific inhibitors. Hence, the detailed characterisation of enzymes of this catabolic pathway at the molecular and atomic level will enable future rational design of inhibitors that may prove useful biological tools and potentially novel antibiotics.

A PhD student working in this project will elucidate the crystal structure and reaction mechanism of the enzyme catalysing the first reaction in the pathway. Another gene in the same gene cluster encodes a protein of unknown function, but likely to be a regulatory enzyme catalysing post-translational modification of the first enzyme to inhibit its activity. The student will thus unveil the function of this regulatory enzyme using mass spectrometry-based kinetic assays and quantitative proteomics. Finally, the effect of the post-translational modification on the structure and activity of the first enzyme will be dissected.

A student in this project will acquire training in gene cloning, site-directed mutagenesis and heterologous gene expression, protein purification and crystallography, enzyme kinetics, circular dichroism, isothermal titration calorimetry, differential scanning fluorescence, and protein and small-molecule mass spectrometry, and analysis of large data sets from proteomics. These are highly sought-after skills in both academic and industrial settings.

The successful candidate will have a 1st-class honours BSc and/or an MSc in Biochemistry or Chemistry, some research experience, and enthusiasm for elucidating enzyme mechanisms for drug development. Candidates should contact Dr da Silva to discuss their application and the project before applying.

Application procedure
In order to apply for this position, please follow the application instructions under http://www.eastscotbiodtp.ac.uk/how-apply-0 to obtain the EASTBIO Application form.

Then, submit the EASTBIO application form and your academic transcripts as part of a formal online application- https://www.st-andrews.ac.uk/study/apply/postgraduate/research/

In the online application form, you will be asked to provide contact details for two academic references. Please ask your referees to use the EASTBIO reference form provided under the link above when preparing their support letter, and to ensure references are provided by the deadline on 6 January 2021.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership View Website.

This opportunity is open to UK and International students and provides funding to cover stipend and UK level tuition. For international candidates, the University of St Andrews will cover the Home-International fee difference. Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.

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