Wolfson Fellow receives MRC Career Development Award

Wolfson Research Fellow, Dr Despoina Mavridou, has recently been awarded a five-year Career Development Award by the Medical Research Council to carry out research that aims to help solve the immense problem of bacterial antibiotic resistance.

She explains the path that has led her to this research:

"After an Undergraduate degree in Chemistry at the University of Athen, I was accepted to the Biochemistry Department in Oxford to carry out my DPhil working with Professors Stuart J Ferguson and Christina Redfield.

At the time my project focused on the formation of disulfide bonds in Gram-negative bacteria, using NMR spectroscopy as well as other biophysical and biochemical techniques to study the protein system that forms these bonds in E. coli.

During my subsequent postdoc position I continued to explore disulfide bond formation but also branched out to study cytochrome c maturation in Gram-negative bacteria, a topic Professor Ferguson's lab has been specialising in for a number of years.

During my ten years in Oxford, I have used a variety of techniques to study multiple protein partners (the two protein systems I worked on consist of four and eight proteins, respectively) and my fascination with bacteria and their ability to adapt and thrive in every environment remained.

In October I was awarded an MRC Career Development Award to start my own group at Imperial College London. My proposed project takes me back to the first protein system I worked on: the DSB system which forms disulfide bonds in all Gram-negative bacteria.

The DSB protein system is responsible for the formation and quality control of disulfide bridges in hundreds of protein substrates. It is a central and essential system because disulfide bonds are crucial for the folding, stability, and function of the majority of proteins populating harsh extracytoplasmic environments like the bacterial cell envelope and surface. Most factors that allow bacteria to be efficient pathogens are dependent on the function of the DSB system, which is therefore intricately involved in bacterial virulence.

Even more importantly, the DSB systems found in pathogens seem to have diversified compared to the protein system found in non-pathogenic bacteria like E. coli; namely many bacterial pathogens encode multiple copies of the key DSB protein players. This implies a specialisation, an adaptation of the system to efficiently handle substrates related to pathogenesis, and this aspect of the DSB system is hugely understudied.

The MRC CDA will allow me to study the role of the DSB system in Gram-negative bacterial pathogens through a three-part approach: I will use Bioinformatics to identify all DSB systems in all Gram-negative bacteria and from there I will map the presence of the DSB system in bacterial pathogens. Through this analysis I will be able to identify underlying common trends in the variation of the system that could lead to novel antibacterial strategies in the future.

Experimentally I plan to use two approaches. I will study the role of the three copies of the central oxidase DsbA in Neisseria meningitidis, a severe human pathogen, and the role of the two copies of the quality control protein DsbD in the opportunistic pathogen Pseudomonas aeruginosa, a bacterium that at the moment is resistant to all available antibiotics.

I will be based in the MRC Centre of Molecular Bacteriology and Infection (CMBI), a cross-faculty, multidisciplinary research centre, comprising members from the Departments of Life Sciences and Medicine. The members of the MRC-CMBI use multidisciplinary approaches and cutting-edge techniques to study bacterial infections at atomic, cellular, and organism levels, with the aim of finding ways of developing new antibiotics, combating antibiotic resistance, and developing effective vaccines.

My MRC CDA will allow me to perform an important transition from classical bacteriology, biochemistry, and protein science to the study of bacterial pathogens and will hopefully enable me to contribute to solving the immense problem of bacterial antibiotic resistance in the future."