By Heather Hobbs
BRINGING YOU THE LATEST NEWS & EVENTS FROM THE SCIENCE INDUSTRY Diamond Synchrotron Helps Reveal Protective Shield of Superbug
Corresponding author, Dr Salgado, added: “I started working on this structure more than 10 years ago, it’s been a long, hard journey but we got some really exciting results! Surprisingly, we found that the protein forming the outer layer, SlpA, packs very tightly, with very narrow openings that allow very few molecules to enter the cells. S-layer from other bacteria studied so far tend to have wider gaps, allowing bigger molecules to penetrate. This may explain the success of C. diff at defending itself.”
The team determined the structure of the proteins and how they are arranged using a combination of X-ray and electron crystallography. Making a natural 2D array crystallise as a 3D crystal was not easy and the crystals had many problems. Dr Salgado explained: “Even when crystals were obtained, not all diffracted well so the Diamond synchrotron was essential for the success of the project. The work relied particularly on I24, the microfocus beamline, to test many hundreds of crystals and screen for the best spot in the best crystal to collect the best data set. Getting native data was not the end of the story as there were no models to allow structure determination. Staff across the MX beamlines at Diamond were always eager to help solve this problem and willing to try new approaches and accommodate requests for specialised beamtime. But the crucial experiment was using the unique long wavelength I23 beamline, which allowed using the native sulphur atoms in SlpA as sources of information required to start building a model.“
Data was collected from beamlines 12, 124 and 104 to build the structural model of the protective armour around C.diffi cile
A team of scientists from Newcastle, Sheffi eld and Glasgow Universities have revealed, for the fi rst time, the structure of the protective armour surrounding the superbug C.dIffi cile, a close knit fl exible layer resembling chainmail, which while preventing molecules from getting in, also provides a new target for drug development. Dr Paula Salgado, Senior Lecturer in Macromolecular Crystallography, who led the research at Newcastle University said: “Excitingly, this opens the possibility of developing drugs that target the interactions that make up the chainmail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell and kill it.”
Together with colleagues from Imperial College and Diamond Light Source, the team was able to outline the structure of the main protein, SlpA, that forms the links of the chainmail and how they are arranged to form a pattern and create this fl exible armour.
The data collected on I23 allowed Senior Beamline Scientist Dr Kamel El Omari to fi nd the positions of the sulphur atoms and generate an initial partial model. This was the starting point that, together with higher resolution data collected at I24 and I04 beamlines at Diamond, allowed Dr Salgado and her team to build the full SlpA structure.
Dr El Omari said: “It was a pleasure to be part of this long standing and exciting project. It is a nice example showing how collaborations and access to state-of-the-art facilities like Diamond Light Source are successfully supporting the scientifi c community.”
So-called superbugs have multiple ways to resist antibiotics and can combine multiple resistance mechanisms. C. diff, is a superbug that infects the human gut and is resistant to all but three current drugs. Not only that, but it becomes a problem when antibiotics are taken, as the good bacteria in the gut are killed alongside those causing an infection. As C. diff is resistant, it can grow and cause diseases ranging from diarrhoea to death due to massive lesions in the gut. Another problem is the fact that the only way to treat C.diff is to take more antibiotics, so the cycle is restarted and many
Image of C.diff armour by Dr Lizah van der Aart (Credit: Newcastle University, UK)
people get repeat
infections.Determining the structure allows the possibility of designing C. diff-specifi c drugs to break the S-layer, the chainmail, and fi ght infections.
From Dr Salgado’s team at Newcastle University, PhD student Paola Lanzoni-Mangutchi and Dr Anna Barwinska-Sendra unravelled the structural and functional details of the building blocks and determined the overall X-ray crystal structure of SlpA. Paola said: “This has been a challenging project and we spent many hours together, culturing the diffi cult bug and collecting X-ray data at the Diamond Light Source synchrotron.”
Dr Barwinska-Sendra added: “Working together was key to our success, it is very exciting to be part of this team and to be able to fi nally share our work.”
Dr Rob Fagan and Professor Per Bullough’s teams at the University of Sheffi eld carried out the electron crystallography work. Dr Fagan said: “We’re now looking at how our fi ndings could be used to fi nd new ways to treat C. diff infections such as using bacteriophages to attach to and kill C. diff cells - a promising potential alternative to traditional antibiotic drugs.”
The work is illustrated in a stunning image by Newcastle- based science Artist and Science Communicator, Dr. Lizah van der Aart.
Structure and assembly of the S-layer in C. diffi cile. P. Lanzoni- Mangutchi et al. Nature Comms. Doi: 10.1038/s41467-022- 28196-w
The paper is published in Nature Communications (www.
nature.com/articles/s41467-022-28196-w)
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Epigenetic Changes have Potential as a Focus for Biomarker Development
Two new studies led by researchers at Turku Bioscience at the University of Turku, Finland, have been able to link epigenetic changes to type 1 diabetes in children, providing potential opportunities for development of biomarkers for the disease.
While certain antibodies detected in children’s blood samples indicate an increased risk of developing type 1 diabetes, the research highlighted that epigenetic changes – those that affect how our genes work, including environmental factors such as exposure to viral infections – were already present in the cells of the childrens immune systems before the antibodies of the disease were detected in their blood.
Professor Riitta Lahesmaa, Director of Turku Bioscience said: “We uncovered previously unknown, early-onset epigenetic changes. They offer us new opportunities to further develop ways to identify children who have a risk of developing type 1 diabetes even before they get sick.”
“Our observations on epigenetics are extremely important as our goal is to develop methods and tools to prevent the onset of type 1 diabetes in children who are at risk of developing the disease,” added Professor Laura Elo. Director of the
Medical Bioinformatics Centre at Turku Bioscience.
In Finland, children’s risk of developing type 1 diabetes is the highest in the world. In addition to the genetic susceptibility, environmental factors have a great signifi cance for developing the disease. The environmental factors include, for example, excessive level of hygiene, biodiversity loss, and environmental toxins.
The newly published studies are based on long-term interdisciplinary research collaboration with international partners. The project has included doctors who are in charge of the patients and also conduct clinical research, researchers in molecular medicine and immunology, and experts in computational science. In the studies, researchers analysed longitudinal samples with deep sequencing covering the entire genome as well as with computational methods and artifi cial intelligence.
“Our research was enabled by close collaboration with Professor Mikael Knip from the University of Helsinki, who coordinates a study funded by the EU. He is also one of the key scientists in the national Type 1 Diabetes Prediction and Prevention (DIPP) project which was a partner in the other study,” said Professor Lahesmaa. The studies [1] were funded
by the Academy of Finland, Juvenile Diabetes Research Foundation (USA), European Union, Business Finland, Novo Nordisk and InFLAMES Flagship.
Professors Lahesmaa and Elo are group leaders of the R&D initiative ‘Innovation Ecosystem Based on the Immune System’ (InFLAMES) which has received €5.6 million funding for 2020– 2023 from the Flagship Programme of the Academy of Finland.
A joint effort of University of Turku and Åbo Akademi University, InFLAMES aims to identify new targets for drug development together with biotechnology and pharmaceutical companies. Focused on joint and coordinated efforts of more than 300 researchers, including several Turku Bioscience research groups –Elo, Eriksson, Ivaska, Lahesmaa, Mattila, Rantakari and Westermarck labs, - it also develops diagnostics so that targeted therapies could be designed for individual patients.
1. Published in Diabetologia and Diabetes Care journals More information online:
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