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MHH biochemist is researching alternatives to antibiotics and has received two million euros from the European Union.
If our immune system cannot cope with a bacterial infection, antibiotics help. However, more and more bacteria are becoming resistant to treatment. The number of deaths resulting from this worldwide stood at more than 1.1 million in 2021. By 2050, an estimated eight to ten million people worldwide are expected to die each year due to antibiotic resistance. The World Health Organisation (WHO) lists the intestinal bacteria of the genera Enterococcus and Escherichia coli, among others, as critical pathogens. A research team led by Dr Timm Fiebig, head of the ‘Microbial Glycobiochemistry and Vaccine Development’ working group at the Institute of Clinical Biochemistry at Hannover Medical School (MHH), is investigating these bacteria, focusing in particular on so-called capsule polymers. They consist of various combinations of many sugars and surround the bacteria like a protective shell. This makes them invisible to the immune system and, at the same time, forms a barrier against certain antibiotics.
In his BESPOKE project, Dr Fiebig aims to decipher the diverse polymer structures. In doing so, he hopes to identify previously unknown approaches for new glycoconjugate vaccines that contain the sugar polymers of the various capsid variants and train the immune system to recognise these antigens. The European Research Council (ERC) is funding the project with a five-year Consolidator Grant worth around two million euros. Grants awarded by the ERC are highly regarded within the scientific community. With the Consolidator Grant, the ERC supports researchers who have already demonstrated excellence in their research.
Many polymer variants
Whilst some strains of Enterococcus and Escherichia coli (E. coli) are beneficial, pathogenic variants cause severe diarrhoea, abdominal pain, urinary tract infections and blood poisoning. If they enter other parts of the body via the bloodstream, they can cause serious infections – such as meningitis. “In our project, we want to shed a little more light on bacterial surfaces and investigate the as of yet unknown polymer structures,” explains Dr Fiebig. And there could be a great many of them. To date, 33 E. coli surface structures are known, but new studies suggest that there are likely around 100 different structures. In addition to the diversity, structure and identity of the cell surface polymers, the researchers also want to investigate how these polymers determine the biological niche that is colonized by a bacterial strain, or the type of infection it causes. Furthermore, they aim to identify which polymers indicate whether a strain belongs to beneficial or harmful bacteria.
Search for the enzymes involved
What sounds so straightforward actually requires a great deal of scientific detective work. At first, the researchers need to identify which genes in the bacterial genome are responsible for the biosynthesis of the various capsule polymers. “That’s not at all straightforward, because DNA contains the information for proteins, but not for the different sugars,” says Dr Fiebig. The team must therefore identify which enzymes encoded in the DNA play a role in the formation of the sugar polymers. “But here too there are various possibilities, because a particular ‘type of enzyme’ can be responsible for the biosynthesis of several different sugar polymers,” the biochemist points out. To make the search a little easier, the research team is therefore focusing primarily on the genetic material of bacteria isolated from patients. The extensive sample material comes from the MHH Institute of Medical Microbiology and Hospital Hygiene and the Twincore Centre for Experimental and Clinical Infection Research, which collect bacterial genomes in a special database accessible to Dr Fiebig and his team. Based on this data, they aim to elucidate the structural diversity of the sugar compounds to which the human immune system is exposed during various types of infection.
Producing vaccines without bacteria
The long-term aim of the BESPOKE project is to create a sort of profile for the polymers. “We could then produce a vaccine from suitable candidates,” explains Dr Fiebig. And this can be done, so to speak, without pathogens. “Elucidating the biosynthetic pathway enables the elegant production of vaccine antigens from widely available and inexpensive precursors in a standard laboratory, without having to cultivate dangerous bacteria in bioreactors,” says Dr Fiebig. This enzyme factory can be recreated in a test tube under safe conditions. On a laboratory scale, Dr Fiebig and his research group have already succeeded in doing this with a vaccine candidate against the bacterium Haemophilus influenzae type b (Hib), which causes infections of the upper and lower respiratory tracts, but also triggers more serious conditions such as middle ear infection, meningitis or sepsis. “In the coming years, we aim to build a versatile ‘toolbox’ for the synthesis of glycoconjugate vaccines against bacterial infections, which will help combat antibiotic resistance and enable a rapid response to bacterial infections.”
For further information, please contact Dr Timm Fiebig, Fiebig.timm@mh-hannover.de, telephone +49 511 532-5212.
Investigating the diversity of bacterial sugar coats: biochemist Dr Timm Fiebig
Copyright: Karin Kaiser/MHH
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