The protective armor of superbug C.difficile revealed
Spectacular structure of chain-mail may explain the success of C.diff at defending itself against antibiotics and immune system molecules

Date:
February 25, 2022
Source:
Newcastle University
Summary:
The close-knit, flexible outer layer - like chain mail - which
protects superbug C.difficile has been unveiled.



FULL STORY ==========================================================================
The spectacular structure of the protective armour of superbug
C.difficilehas been revealedfor the first time showing the close-knit
yet flexible outer layer -- like chain mail.


==========================================================================
This assembly prevents molecules getting in and provides a new target
for future treatments, according to the scientists who have uncovered it.

Publishing inNature Communications, the team of scientists from Newcastle, Sheffield and Glasgow Universities together with colleagues from Imperial College and Diamond Light Source, outline the structure of the main
protein, SlpA, that forms the links of the chain mail and how they are
arranged to form a pattern and create this flexible armour. This opens the possibility of designing C. diff specific drugs to break the protective
layer and create holes to allow molecules to enter and kill the cell.

Protective armour One of the many ways that diarrhea-causing superbug Clostridioides difficile has to protect itself from antibiotics is a
special layer that covers the cell of the whole bacteria -- the surface
layer or S-layer. This flexible armour protects against the entry of
drugs or molecules released by our immune system to fight bacteria.

The team determined the structure of the proteins and how they arranged
using a combination of X-ray and electron crystallography.



========================================================================== Corresponding author Dr Paula Salgado,Senior Lecturer in Macromolecular Crystallography who led the research at Newcastle University said:
"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 against the antibiotics and
immune system molecules sent to attack it.

"Excitingly, it also opens the possibility of developing drugs that
target the interactions that make up the chain mail. If we break these,
we can create holes that allow drugs and immune system molecules to
enter the cell and kill it." One of the current challenges in our fight against infections is the growing ability bacteria have to resist the antibiotics that we use to try to kill them. Antibiotic or more generally, antimicrobial resistance (AMR), was declared by 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 avoid their action -- the so-called
superbugs. Included in these superbugs is C. diff, a bacteria that infects
the human gut and is resistant to all but three current drugs. Not only
that, it actually becomes a problem when we take antibiotics, as the good bacteria in the gut are killed alongside those causing an infection and,
as C. diff is resistant, it can grow and cause diseases ranging from
diarrhea 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 antibiotics,
so we restart the cycle and many people get recurrent infections.

Determining the structure allows the possibility of designing
C. diff-specific drugs to break the S-layer, the chainmail, and create
holes to allow molecules to enter and kill the cell.



========================================================================== Colleagues, Dr Rob Fagan and Professor Per Bullough at the University
of Sheffield carried out the electron crystallography work.

Dr Fagan said: "We're now looking at how our findings could be
used to find 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." 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 difficult 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 finally share our work." The work
is illustrated in the stunning image by Newcastle-based science Artist
and Science Communicator, Dr. Lizah van der Aart.

========================================================================== Story Source: Materials provided by Newcastle_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Paola Lanzoni-Mangutchi, Oishik Banerji, Jason Wilson, Anna
Barwinska-
Sendra, Joseph A. Kirk, Filipa Vaz, Shauna O'Beirne, Arnaud Basle',
Kamel El Omari, Armin Wagner, Neil F. Fairweather, Gillian R. Douce,
Per A.

Bullough, Robert P. Fagan, Paula S. Salgado. Structure and assembly
of the S-layer in C. difficile. Nature Communications, 2022; 13
(1) DOI: 10.1038/s41467-022-28196-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220225085859.htm

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