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Targeting transcription termination/antitermination in Staphylococcus aureus by inhibition of NusB/E/G protein-protein interactions.

  • Full or part time
    Prof M Auer
    Prof R Fitzgerald
  • Application Deadline
    Thursday, December 13, 2018
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Due to antibiotic resistance, many bacterial infections have become almost impossible to treat, particularly multidrug resistant strains for example the ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter. Therefore, the identification of new targets and resistance pathways is essential for developing next-generation antibiotics to combat this. Protein-protein-interactions involved in transcription are an attractive option for pharmacological intervention1. A host of regulatory proteins are involved in this complex pathway, and disruption of this process has been shown to be of therapeutic benefit2. A particular process involved in RNA transcription of some bacteria, called antitermination, which is essential for the production of ribosomal RNA (rRNA), is an interesting target for drug intervention. NusB and NusE are small transcription factors required for the formation of antitermination complexes that carry out rRNA synthesis3,4. Antitermination complex assembly initiates when NusB binds to a newly transcribed conserved RNA sequence in the rRNA operon leader sequence called boxA. Next, a NusB-NusE heterodimer is formed to strengthen the interaction with boxA and facilitate binding of other regulatory factors, and the complex interacts with RNA polymerase (RNAP) via NusE5,6. Since rapid cell proliferation is a characteristic of bacterial infection, small molecules that disrupt NusB-NusE heterodimer formation or interaction with boxA or that inhibit NusB-NusE-boxA interaction with RNA polymerase (RNAP) have potential as lead compounds for novel antibiotics7.
This project will focus on finding and characterise inhibitors of the PPI system NusB-NusE-NusG. S. aureus NusB, NusE and NusG will be produced in collaboration with the Univ. of Bayreuth, Germany. The student will learn and apply several label free biophysical and biochemical affinity selection methods, all available in the Auer lab, to screen fragment- and small molecule libraries to identify binders to, and inhibitors of the NusB-NusE-NusG complexes. These inhibitors will be tested for activity in a newly developed and proprietary 4 color confocal imaging assays of S.aureus infection of macrophages. To determine binding sites of hit compounds, NMR, X-ray crystallography and mass spectrometry methods including deuterium exchange MS and MS-crosslinking will be used. Various computational chemistry approaches will be integrated to support hit to lead activities including ligand based similarity analysis and structure based in-silico screening and design. In the Fitzgerald lab, there is access to a wide array of different S. aureus clinical strains, molecular tools and functional assays for understanding host-pathogen interactions and antibiotic resistance. In addition to multiple opportunities for high quality publications, the student will acquire interdisciplinary knowledge in one of sciences most active fields of targeting drug resistant bacteria. Career progression in academia and industry will be possible after completing the PhD.

Further Information about various assay and screening platforms developed and run by the Auer lab can be found on: https://sites.google.com/view/the-auer-lab-uoe/home.

Fitzgerald Lab: https://www.ed.ac.uk/edinburgh-infectious-diseases/research/themes/molecular-pathogenesis/ross-fitzgerald.

Funding Notes

The “Apply online” button on this page will take you to our Online Application checklist. Please complete each step and download the checklist which will provide a list of funding options and guide you through the application process.

If you would like us to consider you for one of our scholarships you must apply by 12 noon on 13 December 2018 at the latest.

References

Mohanty, B et al. Fragment library screening identifies hits that bind to the non-catalytic surface of Pseudomonas aeruginosa DsbA1. PLoS One 12, e0173436 (2017).
2. Butt, TR & Karathanasi, SK Transcription Factors as Drug Targets: Opportunities for Therapeutic Selectivity. Gene Expr. 4, 319–336 (1995).
3. Drögemüller J, Schneider C, Schweimer K, Strauß M, Rösch P, Knauer SH. Thermotoga maritima NusG: domain interaction mediates autoinhibition and thermostability. Nucleic Acids Research 2017; 45:446-460. DOI: 10.1093/nar/gkw1111
4. Doherty GP, Meredith DH, Lewis PJ Subcellular partitioning of transcription factors in Bacillus subtilis. J. Bacteriol 188, 4101-4110 (2006).
5. Burmann BM, Luo X, Rösch P, Wahl MC, Gottesman ME Fine tuning of the E.coli NusB:NusE complex affinity to BoxA RNA is required for processive antitermination. Nucleic Acids Res 38, 314-326 (2010)
6. Drögemüller J, Strauß M, Schweimer K, Jurk M, Rösch P, Knauer S. Determination of RNA polymerase binding surfaces of transcription factors by NMR spectroscopy. Scientific Reports 2015; 5: 16428-16441. DOI: 10.1038/srep16428
7. Ma C, Yang X, Lewis PJ Bacterial transcription as a target for antibacterial drug development. Microbiology and Molecular Biology Rev 80, 139-160 (2016).

How good is research at University of Edinburgh in Biological Sciences?

FTE Category A staff submitted: 109.70

Research output data provided by the Research Excellence Framework (REF)

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