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Mini Centre for Doctoral Training: Overcoming drug-resistant microbial infection – Targeting the power of Molecular Machines


Project Description

The newly formed “Centre for Structural Medicine” (joint between the Schools of Biological and Chemical Sciences and Medicine and Dentistry) is seeking PhD applicants for their fully funded mini Centre for Doctoral Training (CDT) to start in September 2020.

The School of Biological and Chemical Sciences at Queen Mary is one of the UK’s elite research centres (2014 Research Excellence Framework) and offers a multi-disciplinary research environment. The school has approximately 160 PhD students that have access to a variety of research facilities supported by experienced staff, as well as a range of student support services.

Project Details

Targeting microbial infection via their molecular machines: The rise of microbial and viral infection is an urgent and growing problem. It has emerged as one of the pre-eminent public health concerns of the 21st century. A recent report from the OECD predicts that 2.4 million people in Europe, North America and Australia will die from infections with resistant microorganisms in the next 30 years (Stemming the Superbug Tide, 2018).

Virulence of microbial pathogens is enabled by a suite of sophisticated molecular machines that drive virtually all essential cell functions - from fundamental processes such as DNA replication and protein production to highly specialised multi-component systems required for host-pathogen interactions. Identifying individual machine parts and understanding how they act together is key to recognising major events during the infection process and to developing new drug targets for combating microbial infections. The complex architecture and highly dynamic nature of these molecular machines requires a coordinated cross-disciplinary approach integrating structural, functional and physiological data. To promote such an approach, we have established the “Centre for Structural Medicine” in the Blizard Institute between the Schools of Biological and Chemical Sciences and Medicine and Dentistry.

The PhD students will investigate the architecture and function of molecular machines essential for microbial infection. These will aim to pinpoint novel and functionally critical protein-protein interactions, evolve/screen for biological therapeutics that inhibit these interactions and thus discover new lead antimicrobials. The mini-CDT will be divided into the following themes: molecular machines important (i) pre-infection, (ii) during infection and (iii) post-infection.

The Team

Our Centre incorporates 13 academics and their research groups (each student will be jointly supervised):

Dr. V.Darbari: Mycobacterial lipid import assemblies, bacterial secretion systems.
Dr. C.Engl: Bacterial RNA repair, ribosome function.
Prof. L.Hall: DNA repair mechanism in S.Pneumoniae.
Dr. A.Kang: Directed evolution of human antibodies to P.gingivalis OM vesicles.
Dr. A.Ilangovan: Bacterial DNA replication machinery, conjugative DNA processing systems.
Prof. A.McKinight: Interactions of HIV with the molecular machinery of the host cell.
Dr. E.Main: Directed evolution of microbial inhibitors to Type 3 Secretion System.
Dr. O.Marches: Pathogenic mechanisms of E.coli effector proteins.
Prof. R.Pickersgill: Structural biology of the Type 2 Secretion System.
Dr. B.Stieglitz: Bacterial effectors that manipulate ubiquitination (cell trafficking) within the human cell.
Dr. L.Subramanian: Chromosome biology of fungal pathogens.
Dr. S.Wilkinson: Biochemical/molecular parasitology focusing on the mechanisms & drug treatments of trypanosomes.
Dr. D.Wareham: Antimicrobial resistance mechanisms in nosocomial bacterial.

Training and development

The studentships are multi-disciplinary and will involve a combination of techniques such as molecular biology, microbial physiology (involving microbial genomic manipulations using techniques such as CRISPR), recombinant protein production, biochemical/biophysical assays [e.g. C.D. spectroscopy and ITC], directed evolution, protein structure determination (X-ray crystallography or Cryo Transmission Electron Microscopy), drug discovery involving small molecule screening etc. As such, it will provide opportunities for training in a wide range of contemporary molecular biology and biochemistry techniques and will equip the successful applicants with a highly desirable portfolio of laboratory skills and associated transferable skills.

Entry Requirements

Applications are invited from outstanding candidates with or expecting to receive a first or upper-second class honours degree an area relevant to the project: e.g. the Biosciences – Molecular Biology, Biochemistry, Biophysics and Biomedical Sciences. A masters degree is desirable, but not essential. In particular, applicants should have direct experience of some of the following: molecular biology, recombinant protein production, biochemical/biophysical assays [e.g. C.D. spectroscopy and ITC], directed evolution or protein structure determination (protein crystallisation/Electron Microscopy).

Applicants from outside of the UK are required to provide evidence of their English language ability. Please see our English language requirements page for details.

Please visit our website for information on the applications process

Funding Notes

The mini-CDT is open to UK/EU applicants and are funded by Queen Mary University of London. The funding will cover tuition fees, and provide an annual tax-free maintenance allowance for 3 years at the Research Council rate (£17,009 in 2019/20).

References

Tang J1, Wang L, Markiv A, Jeffs SA, Dreja H, McKnight Á, He M, Kang AS. “Accessing of recombinant human monoclonal antibodies
from patient libraries by eukaryotic ribosome display.” (2012) Hum Antibodies 21(1-2),1-11.

Singh SK, Boyle AL, Main ERG (2013). “LcrH, a class II chaperone from the type three secretion system, has a highly flexible native structure.” J Biol Chem vol. 288, (6) 4048-4055.

Gu S, Vladimir VE, Shaw R, Pickersgill RW, Garnett JA (2017). “The role of intrinsic disorder and dynamics in the assembly and function of the type II secretion system.” BBA - Proteins and Proteomics vol 1865, Issue 10, 1255-1266.

Glyde R, Fuzhou Y, Darbari VC, Zhang N, Buck M, Zhang X(2017). Structures of RNA Polymerase Closed and Intermediate Complexes Reveal Mechanisms of DNA Opening and Transcription Initiation. Molecular Cell, Vol 67, 1, 106-116.e4.

Kliza K, Taumer C, Pinzuti I, Franz-Wachtel M, Kunzelmann S, Stieglitz B, Macek B, Husnjak K(2017). “Internally Tagged Ubiquitin: a Tool to Identify Linear Polyubiquitin-modified Proteins by Mass Spectrometry.” Nature Methods 14, 504–512

Wareham DW, Momin MHFA, Phee LM, Hornsey M, Standing JF (2019). Cefepime/sulbactam as an enhanced antimicrobial combination therapy for the treatment of MDR Gram-negative infections. J Antimicrob Chemother, Vol 75, 1, 135–139

McCoy LE, McKnight Á(2017). Lessons learned from humoral responses of HIV patients. Curr Opin HIV AIDS vol. 12, (3) 195-202.

Engl C, Schaefer J, Kotta-Loizou I, Buck M (2016). Cellular and molecular phenotypes depending upon the RNA repair system RtcAB of Escherichia coli. Nucleic Acids Research Vol 44, 20, 16, 9933–9941

Dittani A, Wilkinson SR (2019). Deciphering the interstrand crosslink DNA repair network expressed by Trypanosoma brucei. DNA Repair vol. 78, 154-166.

Ilangovan, A., Kay, C.W.M., Roier, S., El Mkami, H., Salvadori, E., Zechner, E.L., Zanetti, G., andWaksman, G. (2017). “Cryo-EM Structure of a Relaxase Reveals the Molecular Basis of DNA: Unwinding during Bacterial Conjugation.” Cell 169, 708-721 e712

How good is research at Queen Mary University of London in Biological Sciences?

FTE Category A staff submitted: 23.39

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

Click here to see the results for all UK universities

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