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A new study led by Dr. Antonella Fioravanti in Professor Han Remaut's laboratory (VIB-VUB Structural Biology Center) has shown that removing shielding from the bacteria that causes anthrax slows its growth and negatively affects its ability to cause diseases. This work will be published in the prestigious journal Nature Microbiology, which can pave the way for new and effective ways to combat anthrax and various other diseases.
Coal is a deadly and very resistant disease caused by the bacterium Bacillus anthracis, which is responsible for the formation of spores. Historically, it was a major cause of death in humans and livestock. Today, it is much less common thanks to better hygiene and vaccination of livestock. Nevertheless, coal remains a natural disease that affects wildlife and livestock around the world. In humans, it is a health problem mainly in the form of a skin infection in persons handling contaminated animal products, or more rarely a fatal systemic infection when ingested or inhaled.
The hardness of the spores and the lethality of an anthrax infection by inhalation have unfortunately stimulated its development as a biological weapon in the mid-twentieth century. Although the development and stockpiling of anthrax as a bio-weapon has been banned by the international community, these regulations are sometimes violated. Because treatment options are limited and in most cases inefficient, this means that coal remains a potential threat of bioterrorism.
As part of its strategy to escape the arms of the immune system, the anthrax bacteria is covered with complex and dynamic armor. A poorly understood component of this armor is the sap layer, a single layer of protein that forms a shell around the bacteria. In this study, researchers successfully applied Nanobodies® – small fragments of antibodies – to control the badembly of bacterial weave and study its structure. Nanobodies have not only effectively prevented the formation of armor, but have also proved very effective in breaking down existing S layers. When applied to living bacteria, decomposition of the armor slowed bacterial growth and resulted in radical changes to the surface of the bacterial cell.
Fioravanti, who led the research, shares his enthusiasm: "I was on the moon, I created these nanobodies as a tool to study the sap sap layer, but they would also inhibit bacterial growth." .
The effects were so striking that the Nanobodies were tested as treatment in B. anthracis infected mice. "The results were amazing – all the treated mice found deadly anthrax in a few days," says Filip Van Hauwermeiren, who conducted the studies on the infection. "We had studied ways to stop the lethality of anthrax but we had never seen as striking effects as with these nanobodies," adds his supervisor Mohamed Lamkanfi ( formerly VIB-UGhent Research Center for Inflammation, now at Janssen Pharmaceutica and at the University of Ghent).
These discoveries represent a step forward in a quest that began in the 19th century. When Robert Koch proved in 1876 that bacteria were agents of infectious diseases, he studied B. anthracis. In 1881, Louis Pasteur showed the public that exposure to inactivated B. anthracis protected cattle against anthrax. Nevertheless, the general public does not have access to a safe vaccine against anthrax and it is problematic to treat acute infections in unvaccinated persons. It requires lengthy treatments with antibiotics that have low success rates. The therapeutics derived from the Nanobodies discovered in this study could one day fill this therapeutic gap. In addition, targeting the S-layer with nanobodies may prove effective in the fight against other bacteria with S-armor. For example, the laboratory is currently studying the S-layer targeting nanobodies in Clostridium difficile that causes life-threatening colitis.
Finally, the success of the experiments in this study prompted researchers to look for other vulnerable targets on the surface of bacterial cells. Professor Han Remaut explains, "Proteins on the surface of bacteria are interesting antibacterial targets because they are directly accessible, and the targeting of these proteins means that we need to worry less about the different ways in which bacteria prevent drugs from getting into the body. the cell."
Reference: The structure of the S-layer protein, SAP, reveals a mechanism of therapeutic intervention against anthrax, Fioravanti et al., Nature Microbiology 2019
This research was funded by VIB and FWO Flanders through a project grant G028113N.
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