The spectacular structure of the chain-mail may explain C.diff's success in defending itself against antibiotics and immune system molecules.
The spectacular structure of the protective shell of the superbug C.difficile is showing for the first time a close-knit but flexible outer layer - like chain mail.
According to the scientists, this assembly prevents molecules from getting inside and provides a new target for future treatments.
Publishing in Nature Communications, the team of scientists from the Universities of Newcastle, Sheffield and Glasgow, along with collaborators from Imperial College and the Diamond Light Source, outline the structure of the key protein, SLPA, that forms the chain mail links and how they are one. Arranged to make patterns and make this flexible armor. This opens up the possibility of designing C. Breaks down the protective layer that separates specific drugs and creates holes to allow molecules to enter and kill the cell.
Protective cover
One of the many ways the diarrhea-causing superbug Clostridioides difficile can protect itself from antibiotics is through a special layer that covers the entire bacterial cell – the surface layer or S-layer. This flexible shield protects against penetration of drugs or molecules released by our immune system to fight bacteria.
The team used a combination of X-ray and electron crystallography to determine the proteins' structure and how they are arranged.
Dr. Paula Salgado, Senior Lecturer in Macromolecular Crystallography, who led the research at the University of Newcastle, said: "I started working on this structure 10 years ago, it has been a long, arduous journey but we have found something really exciting. Surprisingly, we found that the protein that makes up the outer layer, SLPA, is very tightly packed with very narrow pores that allow very few molecules to enter the cells. Other bacteria have wide gaps in the S-layer through which larger molecules can enter. This explains C.diff's success in defending itself against antibiotics and molecules of the immune system sent to attack it. Can do.
"Excitingly, this also opens up the possibility of developing drugs that target the interactions that create chain mail. If we break these, we can create holes that allow drugs and immune system molecules to enter the cell." and allow him to kill."
One of the current challenges in our fight against infections is the growing ability of bacteria to resist the antibiotics we use to try to kill them. Antibiotic or, more generally, antimicrobial resistance (AMR), was declared by the WHO as one of the top 10 global public health threats facing humanity.
Different bacteria have different mechanisms to resist antibiotics and some have multiple ways to evade their action – the so-called superbugs. These superbugs include C. diff, a bacteria that infects the human gut and is resistant to all except three existing drugs. What's more, it actually becomes a problem when we take antibiotics, as the good bacteria in the gut are killed along with those causing the infection and, as in C. diff is resistant, it can grow and cause diseases ranging from diarrhea to death. Massive wound in the intestine. Another problem is that the only way to treat C.Diff is to take antibiotics, so we start the cycle all over again and many people get recurrent infections.
Determining the structure allows the possibility of C. intraspecific drugs to break down the S-layer, chainmail, and create holes to allow molecules to enter and kill the cell.
The electron crystallography work was carried out by colleagues at the University of Sheffield, Dr. Rob Fagan and Professor Per Bulow.
Dr. Fagan said: "We are now looking at how our findings can be used to find new ways to treat C. infections such as using bacteriophages to attach to and kill cells of C. diff - conventional A promising potential alternative to antibiotics."
From Dr Salgado's team at the University of Newcastle, PhD students Paola Lanzoni-Manguchi and Dr Anna Barvinska-Sendra uncovered 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 difficult bugs and collecting X-ray data at the Diamond Light Source Synchrotron."
Dr. Barvinska-Sendra said: "Working together was the key to our success, it is very exciting to be part of this team and finally be able to share our work."
The work is illustrated in a stunning image by Newcastle-based science artist and science communicator, Dr Liza van der Art.
References: Paola Lanzoni-Manguchi, Oshik Banerjee, Jason Wilson, Anna Barwinska-Sendra, Joseph A. "Structure 1 and assembly of the S-layer in C. difficile" by Kirk, Philippa Vaz, Shauna O'Berne, Arnaud Busley. Kamel L'Omari, Armin Wagner, Neil F. Fairweather, Gillian R. Duce, per A. Bullo, Robert P. Fagan and Paula S. Salgado, 25 February 2022, Nature Communications.