David Blow Prize success for Dr Ivo Tews
Cyclic Nucleotides in Bacterial Biofilms
Bacterial biofilms are sessile microbial communities recognised for compromising health. Biofilm formation is a bacterial persistence mechanism that can lead to chronic infection in human patients, with associated morbidity and mortality. Bacteria in biofilms are a major health problem as they are highly tolerant against antibiotic treatment.
Our research aims to understand the mechanisms that promote bacteria to disperse from the biofilm state, reducing chronic infection and lowering antibiotic tolerance. A central regulator in this process is the bacterial signalling molecule cyclic di-guanosine-mono-phosphate, c-di-GMP. Our research is focussed on the control of the c-di-GMP balance, and we have determined the first structure of a dual active enzyme MorA that can both synthesise and break-down c-di-GMP. We are studying the activation of phospho-diesterase enzymes that are central in biofilm dispersal.
Understanding how c-di-GMP levels impact on biofilm development provides a novel opportunity to target bacterial resistance to antibiotics. Our efforts integrate with the efforts of the
National Biofilms Innovation Centre
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Bacterial Warfare The scientists tackling antibiotic resistance
Bacterial nutrient acquisition
To understand bacterial adaptation, we study bacterial enzymes and ABC transporters. The multi-disciplinary approach brings together structural biology, cell biology and marine microbiology (National Oceanography Center).
To understand how bacteria thrive under extreme conditions of nutrient depletion we study iron binding proteins that are important for iron uptake and can also perform intracellular functions. Structural insight derives a novel model of iron homeostasis in Trichodesmium, a cyanobacterium accounting for approximately half of the total marine nitrogen fixation worldwide.
Our work is of fundamental importance to better understand how bacterial adaptation strategies can be exploited for biotechnology and future biofuel technologies, and how they might impact on survival mechanisms in human pathogens.
Methods development
The discipline of macromolecular crystallography is at an exciting juncture that is dependent on the development of insightful experiments that are driven by a fast-evolving technology.
As a partner in Diamond’s VMX project we will reduce demands on sample amount by development of nano-crystallography. Together with advances in data collection and analysis we are already adding time resolution to the crystallography, to provide better insight into molecular mechanisms, and to better represent and understand biological systems.
We develop methods in multi-crystal serial crystallography and study the effects of radiation-induced damage in biological samples. To improve crystallographic data collection and data analysis, we are closely linked up with CCP4, a computing suite that has revolutionised the speed and ease of applying X-ray crystallography to solve healthcare, biological and medical problems.
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Southampton research team invited as first users to new state-of-the-art facility
First users on VMXm
CCP4 Collaborative Computational Project No. 4 Software for Macromolecular X-Ray Crystallography
Immunology Research
Structural biology provides fundamental mechanistic insight that underpins and greatly enhances collaborative research.
We have generated a better understanding of lipid antigen presentation, a process that in the human immune system is not well understood. Our structures of protein-lipid complexes provide an essential basis for computational chemistry and the discovery of cholesterol-esters as an entirely novel class of immune ligands (with Dr Mansour, Prof Elliot, Medicine and Prof Essex, Chemistry). This has led to a paradigm shift in the field of antigen presentation.
The field of antibody therapy is not only today’s favourite recipe for creating blockbuster drugs in autoimmune disease but also a realistic hope to cure specific cancers, employing our own immune system in the task of fighting a tumour. We provide a structural interpretation of pharmaceutical antibodies (with Prof Cragg, Prof Glennie, Dr White, Medicine). We further have developed a novel method combining Small Angle X-ray Scattering (SAXS) and Molecular Dynamics simulation (with Prof Essex, Chemistry).
