Professor David I Roper FRSC

Contact Details

School of Life Sciences, University of Warwick

Scientific Background

Research Interests

Research in my group is focused on the way in which pathogenic bacteria make their cell walls to grow, how that is related to the ways in which they divide and reproduce and also the relationship of these processes to the discovery and resistance to antibiotics:

Peptidoglycan Biosynthesis: The majority of my work is concentrated on understanding the molecular mechanisms that underpin the biosynthesis of peptidoglycan pathogens with particular emphasis on the way in which cell shape is determined and controlled by RodA-PBP and the wider elongasome. This involved coordination of processes from inside to outside the cell membrane
Bacteria Cell division: Cell division is the largest morphological change that any cell undergoes and has common elements in all forms of life. In bacteria this is controlled by a dynamic complex of proteins, many of which are located at or in the cell membrane making their study and analysis challenging. FtsZ and the proteins which interact are of key interest in that respect.
New antibacterial drug discovery: Our studies on cell division and their linkage to peptidoglycan synthesis has an intimate connection to the targets of existing and potentially future antimicrobial drugs. We are investigating a number of these including the potential of the lipid II polymerisation process as a target for such drugs.
Molecular Mechanisms of Antibiotic resistance: We are interested in the molecular mechanisms of antibiotic resistance, in relation to the biosynthesis of the cell wall including the mode of action of the lipid II sequestering antibiotic, vancomycin and our discovery of the way in which D-cycloserine targets three different aspects of peptidoglycan biosynthesis.

Scientific Inspiration

At school I loved all the sciences so took physics, chemistry, and biology all at A-level. My love of making things as well lead me to an interest in engineering, but alas a lack of A-level maths brought that university aspiration to an abrupt end. Since Chemistry and Biology were my best subjects, the next best thing was a degree in Biochemistry which took me to Cardiff and then Leicester to do a PhD at the start of the molecular biology revolution. At Leicester, I also became interested in X-ray crystallography and moved to a postdoc research position followed by independent MRC fellowship at the York Structural Biology Lab. A whole host of wonderful and inspirational people have helped moulded me into the molecular and structural microbiologist that I am today before coming to Warwick as a lecturer and now Professor of Biochemistry. I pride myself in still being active at the bench so that I can properly connect to the people and understand their challenges in the lab and support them wherever I can. My ethos is that science should be both challenging and fun, I hope that is a constant in my research world and those around me. My research is focussed on how bacteria divide and build their cell walls at the same time, which is the target for existing and we hope, many future antibiotics. This focus connects us with a very important biomedical issue and ensures connections to a world-wide collaborative community. Finally, I can call myself an engineer, I just do it at a molecular level.

Research Groups

Roper Group

Microbiology & Infectious Disease

Health GRP

Warwick Antimicrobial Interdisciplinary Centre

Supervision Style

In three words or phrases: Team science, approachable, supportive

Provision of Training

I pride myself in still being active at the bench so that I can properly connect to the people and understand their challenges in the lab and support them wherever I can. In that way I can best appreciate the needs and issues my students face so that we can solve them together. My ethos is that science should be both challenging and fun, I hope that is a constant in my research world and those around me.

Progression Monitoring and Management

I don’t have a prescriptive and formal attitude to supervision but do want me students to come and discuss their projects with me whenever they can. We do have biweekly lab meetings which are meant to be interactive and inspiring. Science works best through communication, interaction, and collaboration. Whilst I’m busy I will always make time for you and your work is more important than any task I’m doing in my office.

Communication

I make myself available by phone, WhatsApp, email, teams and just plain old knock on the door pretty much anytime. I was on sabbatical for a year in the US recently and communicated by teams/skype/whatsapp with the research group most of that time. Everyone felt supported in my absence and knew that I was there for them. Whilst I may email you in the dead of night with some totally genius idea, I don’t expect an instant answer, nor should you in return! We are in this together as a team, its my job to get the best out of you by recognising your strengths and weaknesses and harnessing those to their best effect to train you how to be a successful scientist.

PhD Students can expect scheduled meetings with me:

In a group meeting

At least once a month but more normally once per fortnight. My office is open all the time.

In year 1 of PhD study

At least once per month but I prefer a more informal “come and chat anytime” approach.

In year 2 of PhD study

At least once a month but more normally once per fortnight. My office is open all the time.

In year 3 of PhD study

At least once per month but I prefer a more informal “come and chat anytime” approach.

These meetings will be a mixture of face to face or via video chat or telephone as required. I am usually contactable for an instant response on every working day.

Work Pattern

The timing of work in my lab is completely flexible, but I do have an expectation that students should be here by 10am and will work whatever hours they need to. Flexibility is key, if you are going to be away just tell me so I know what is going on.

Notice Period for Feedback

I need at least 1 weeks’ notice to provide feedback on written work of up to 5000 words.

Project Details

Prof Roper is the supervisor for the below project:

Understanding bacterial cell wall synthesis and its linkage to cell division for next generation antibiotic drugs

Secondary Supervisor(s):Dr Seamus Holden(SLS),Phill Stansfeld(SLS & Chemistry),Dr Allister Crow(SLS),Dr Matt Jenner(Chemistry) or Professor Tim Dafforn (Birmingham) dependent on project undertaken

University of Registration:University of Warwick

BBSRC Research Themes:

Understanding the Rules of Life (Microbiology,Structural Biology)
Integrated Understanding of Health (Pharmaceuticals)

Apply here!

Deadline: 23 May, 2024

Project Outline

Antimicrobial Resistance (AMR) is now widely understood to be a global healthcare emergency, exacerbated by many socio-economic factors. This includes the decline in new drug development due to disengagement from the sector by the major pharmaceutical companies resulting in a renewed emphasis on academic engagement in discovery and understanding of how resistance develops. Of all the targets for antibiotics and resistance development, the biosynthesis of the bacterial cell wall and its linkage to cell division is of particular significance it is the entry point for all antibiotics into bacteria as well as the target for the mainstay of antimicrobial chemotherapy: the b-lactams.

Outside the cytoplasmic membrane of all bacteria, there is a sugar-based polymer called peptidoglycan (PG) crosslinked by peptide bridges, which gives the cell wall strength, rigidity, cell shape characteristics and is a scaffold for a multitude of other molecular structures. Disruptions of the PG structure itself or its biosynthetic precursors by antibiotics, can result in cell lysis (bacteriolytic effect) or cessation of bacterial cell growth (bacteriostatic effect). Recently there has been a renascence in our understanding of the biosynthesis of the cell wall and how this is intimately linked to cell division¹. Whilst we have recognised this process for decades², the molecular interactions that are vital and underpin the biology of this process, are only just starting to be properly addressed.

The biosynthesis of PG requires the polymerisation of its lipid linked disaccharide-pentapeptide monomer unit: lipid II into a glycan polymer³ by the glycosyltransferase activity of either Class A penicillin binding proteins¹ (PBPs e.g. E.coli PBP1b) of by Shape elongation and division proteins (SEDs: e.g. RodA) in association with Class B PBPs. A cross linked PG layer is then produced by the formation of peptide bonds between the pentapeptides on adjacent glycan strands. This is catalysed by the transpeptidase activity of Class A alone or complexes of SEDs proteins with class B PBPs. This latter activity is inhibited directly by beta-lactams whilst the former offers exciting new opportunities for antibiotic drug discovery⁴.

The biosynthesis of PG requires the polymerisation of its lipid linked disaccharide-pentapeptide monomer unit: lipid II into a glycan polymer³by the glycosyltransferase activity of either Class A penicillin binding proteins¹(PBPs e.g. E.coli PBP1b) of by Shape elongation and division proteins (SEDs: e.g. RodA) in association with Class B PBPs. A cross linked PG layer is then produced by the formation of peptide bonds between the pentapeptides on adjacent glycan strands. This is catalysed by the transpeptidase activity of Class A alone or complexes of SEDs proteins with class B PBPs. This latter activity is inhibited directly by beta-lactams whilst the former offers exciting new opportunities for antibiotic drug discovery⁴.

In our laboratory we are focussed on several major aspects of this process including how the cell wall PG is made by the SEDs-Class B PBP complexes and how the process of cell division is coordinated with PG biosynthesis in both Gram-positive and Gram-negative pathogens.

We have recently solved the Cryo-EM structure of the cell elongation specific E.coli RodA-PBP2⁵(see below) and are working in collaboration with research groups who have solved the structure of the divisome specific FtsW-PBP3 complex⁶and have revealed mechanistic evolutionary relationship with other cell wall biosynthetic proteins that utilise a undecaprenyl phosphate carrier lipid substrates⁷. By understanding these factors at a molecular level we hope to bring new biological understanding of the processes involved and discover new route to future antimicrobials.

We use a variety of cutting-edge approaches to study this as well as collaboration with groups across the world in this research to allow a completein-vivotoin-vitroapproach. Importantly, our laboratory has two technological advantages over others including the ability to make the PG precursor lipid II allowing functional study of these proteins as enzymes and non-detergent methods to extract the membrane proteins involved in their native lipid environment⁸allowing structural elucidation of their interactions at a molecular level.

The project will suit a student interested in microbiology, antibiotic resistance and biochemistry. Techniques used in this project can include basic microbiology, molecular biology includingin-vivomutant generation using CRISPR techniques, high resolution light and fluorescent microscopy of the resulting phenotypes to protein chemistry and structural biology including X-ray crystallography, Cryo-EM microscope or Mass spectrometry.

The ultimate PhD project will be developed with the student according to their interests and skill set with in a high collaborative research team environment. Further detail and project areas will be advertised onhttps://warwick.ac.uk/fac/sci/lifesci/research/droper/research/. We urge students interested in the project to get in contact at earliest possible opportunity and engage in mini project opportunities (david.roper@warwick.ac.uk).

References

Typas, A., Banzhaf, M., Gross, C. A. & Vollmer, W. From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nature reviews. Microbiology 10, 123-136, doi:10.1038/nrmicro2677 (2011).
Park, J. T. & Strominger, J. L. Mode of action of penicillin. Science 125, 99-101 (1957).
Galley, N. F., O'Reilly, A. M. & Roper, D. I. Prospects for novel inhibitors of peptidoglycan transglycosylases. Bioorg Chem 55, 16-26, doi:10.1016/j.bioorg.2014.05.007 (2014).
Zuegg, J. et al. Carbohydrate scaffolds as glycosyltransferase inhibitors with in vivo antibacterial activity. Nature communications 6, 7719, doi:10.1038/ncomms8719 (2015).
Nygaard, R. et al. Structural basis of peptidoglycan synthesis by E. coli RodA-PBP2 complex. Nature communications 14, 5151, doi:10.1038/s41467-023-40483-8 (2023).
Kashammer, L. et al. Cryo-EM structure of the bacterial divisome core complex and antibiotic target FtsWIQBL. Nat Microbiol 8, 1149-1159, doi:10.1038/s41564-023-01368-0 (2023).
Ashraf, K. U. et al. Structural basis of lipopolysaccharide maturation by the O-antigen ligase. Nature 604, 371-376, doi:10.1038/s41586-022-04555-x (2022).
Teo, A. C. K. et al. Analysis of SMALP co-extracted phospholipids shows distinct membrane environments for three classes of bacterial membrane protein. Sci Rep 9, 1813, doi:10.1038/s41598-018-37962-0 (2019).

Techniques

Basic microbiology and phenotyping of in-vivo mutants
DNA cloning and site-directed mutagenesis.
Protein expression and chemistry
X-ray crystallography, CryoEM microscopy, Mass spectrometry
High throughut and analytical assay design and development

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