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Hiding in plain sight, but perhaps not for long
12-11-2018
by Jeffrey Bouley  |  Email the author
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MANCHESTER, U.K. & TÜBINGEN and BRAUNSCHWEIG, Germany—Staphylococcus aureus is a killer worldwide, particularly methicillin-resistant S. aureus (MRSA). But pushing back against the bacterium is a team of scientists from the University of Manchester, the University of Tübingen and the German Center for Infection Research (DZIF), who recently reported that they have decoded the structure and function of a previously unknown protein used by S. aureus to cloak itself from the attention of the human immune system and avoid being attacked by it.
 
Better yet, this discovery seems to be applicable to other pathogens that may use the same or similar methods, which could be a boon to fighting drug-resistant bacteria of multiple kinds.
 
The team, led by Prof. Andreas Peschel and Prof. Thilo Stehle of the University of Tübingen, outlined their result in a study published recently in the journal Nature, under the title “Methicillin-resistant Staphylococcus aureus alters cell wall glycosylation to evade immunity.” Normally, they note, the human immune system can deal with pathogens likes bacteria or viruses just fine, but there are times the body’s defenses fail, especially in immunocompromised patients. Meanwhile, most antibiotics ineffective against resistant pathogens, and effective replacement antibiotics and/or protective vaccines against MRSA and similarly dangerous pathogens are still far in the future.
 
Hence this research, because, as the team stresses, a precise understanding of the defense mechanisms could lead to new therapies against MRSA and other such bacteria sooner. And in the discussion coming out of this research, what the team’s scientists are doing is describing how MRSA bacteria become “invisible” to the immune system. They were able to show that many of the particularly frequent MRSA bacteria have acquired a previously unknown protein that prevents the pathogens from being detected by antibodies. The Tübingen scientists gave the protein the name teichoic acid ribitol P (TarP).
 
“TarP alters the pattern of carbohydrate molecules on the pathogen surface in a so far unknown way,” explained Peschel, who is part of the Interfaculty Institute of Microbiology and Infection Medicine at the University of Tübingen. “As a result, the immune system is unable to produce antibodies against the most important MRSA antigen, teichoic acid. The immune system is ‘blinded’ and loses its most important weapon against the pathogen.”
 
The researchers are working from the presumption that the bacterial camouflage is the result of an exchange between the pathogens and their natural enemies, known as bacteriophages. Phages are a class of viruses that attack bacteria, use them as host cells and feed on them. In this case, phages seem to have reprogrammed their host using the TarP protein and thus altered the surface of the bacterium.
 
The first authors of the study, David Gerlach and Yinglan Guo, succeeded in clarifying the mechanism and structure of TarP. “We now have a detailed understanding of how the protein functions as an enzyme on the molecular level,” said Gerlach. They add that the structure-function analysis of TarP forms an excellent basis for the development of new drugs that block TarP, allowing the immune system to detect the pathogens.
 
“The discovery of TarP came as a complete surprise to us. It explains very well why the immune system often has no chance against MRSA,” added Stehle, who works in the Interfaculty Institute of Biochemistry. “The results will help us to develop better therapies and vaccines against the pathogens.”
 
In other news released recently from the University of Manchester regarding the war against bacterial threats, researchers at The University of Manchester’s School of Chemistry say they have described a new pathway for antibiotic production that includes an enzyme called a carboxylase, which adds CO2 to a precursor molecule producing an antibiotic called malonomycin. The point of using this biosynthetic process to produce an antibiotic is that it could possibly lead to the discovery and development of other drugs, helping in the fight against drug-resistant pathogens. The work was carried out in collaboration with the University of Cambridge and is being published in Nature Catalysis under the title “A vitamin K-dependent carboxylase orthologue is involved in antibiotic biosynthesis.”
 
“The rapid rise of antibiotic-resistant pathogens is one of the foremost global health concerns of modern times,” said .Prof. Jason Micklefield, who specializes in and teaches chemical biology at the Manchester Institute of Biotechnology. “Now, using a combination of bioinformatics, gene editing and in-vitro experiments, we have discovered a highly unusual biosynthetic pathway to the antibiotic malonomycin. This could pave the way for a new kind of antibiotic production process.”
 
The team originally became interested in malonomycin because it has a highly unusual chemical structure. It possesses potentially useful antimicrobial activity and has already attracted industrial attention. However, despite the interest in this antibiotic, very little was known about the biosynthesis of malonomycin, until now.
 
The researchers found that CO2 was introduced into the malonomycin structure by a carboxylase enzyme that has never been characterized in bacteria before. Malonomycin carboxylase is most similar to a carboxylase enzyme in human cells which uses vitamin K to add CO2 to proteins in our bodies, triggering essential physiological responses including blood coagulation.
 
Clinically important anticoagulant drugs, such as warfarin, work by blocking the function of the human vitamin K-dependent carboxylase. Added Micklefield: “We were very surprised to find an antibiotic-producing carboxylase enzyme in bacteria that was similar to the human carboxylase responsible for blood clotting. We are now optimistic that our findings might lead to the discovery of new antibiotics, and may also provide new ways of making antibiotics which are urgently needed to combat emerging drug-resistant pathogens.”
 
Code: E12121804

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