A study published last week in Nature tells the story of an unusual type of photography: bacterial photography. Researchers have taken a high-precision photo of the cell wall of deadly bacteria. This is a significant step towards understanding bacteria better and advancing research on antibiotic resistance.

Science has been studying bacteria for decades. Yet, there’s still a lot to understand about some essential parts of these microbes, namely the cell wall. Some bacteria (known as Gram-positive) have thicker cell walls enriched with peptidoglycan, a component made of sugars and amino acids. Some antibiotics kill harmful bacteria by stopping their ability to build their cell walls with this component. So, targeting it could be useful to come up with new antibiotics.

However, if scientists do not know what the cell wall entirely looks like, how could they target it?

Taking photographs of bacteria could solve the issue and this is where the University of Sheffield comes into the narrative. We talked to Laia Pasquina, a PhD student that worked on “photographing” the cell wall with a bit of an upgrade – instead of a camera, she used Atomic Force Microscopy.

Laia Pasquina, physicist (almost) turned biologist is the first author of the paper Photo: Laia Pasquina

Q: What is Atomic Force Microscopy?

Atomic Force Microscopy is a high-resolution microscopy tool. It mainly works as a very sharp needle that scans over the surface of a sample (in this case, bacteria). It then has a mechanism that reads how the needle moves up and down with the surface on the sample. An analogy would be an old vinyl player. This technique allows us to obtain 3D images of the surface of our sample. However, the results can be tricky to interpret, so we had to make our own image analysis routines to get quantitative information from our images.

Q: What were you looking for while doing this research? What were your goals?

Our goal, overall, was to provide a unified model for the cell wall architecture of Gram-positive bacteria. 

We first focused our attention on studying living cells of Staphylococcus aureus using Atomic Force Microscopy. Dr Jonathan Burns did the main part of this work (before I joined the group).

The results gave us information about the cell wall architecture on the outer part of the bacterial cells. However, as Atomic Force Microscopy is a surface technique, we could not obtain information about the architecture on the internal part of the cell wall. Thus, when I joined the group, my main goal was to optimize an appropriate imaging technique to study the internal architecture of the cell wall. Then, I and other researchers (Dr Raveen Tank, Dr Robert Turner, and Dr Sandip Kumar) focused our attention to repeat these experiments with other organisms.

Q: What is the significance of this work? 

The experiments were successful (after more than 10 years of perfecting our expertise) and we finally obtained the different architectures of the cell wall of bacteria.

Previous textbook images always depicted the cell wall as being very uniform and completely ordered, forming an impenetrable wall as if it was made of bricks. However, our findings shed light into decades of guessing, by providing direct images of the cell wall with powerful resolution. The figure we have shows that the cell is constantly modifying and dynamically changing the cell wall structure. This happens so that the cell wall can accommodate the cell’s needs.

Images of peptidoglycan in living S. aureus Photo: Laia Pasquina

Q: How do you think people will benefit from this work in the long term?

This is extremely beneficial for the Microbiology field because we are finally getting some insights into the complexity of this part of the cell. The first step towards finding better antibiotics is to understand its main target, the cell wall. This will be crucial long term because of the rising problem of antimicrobial resistance. Without fundamental knowledge like our work, the scientific community will not be able to produce better treatment for infections that are becoming resistant to our current antibiotics. Both approaches are needed: the focus on making and mass-screening new potential antibiotics, and the knowledge and understanding of how a healthy bacterial cell looks like. 

At the same time, this work represents a benchmark for the use of Atomic Force Microscopy on living organisms and in Microbiology. As this is a relatively recent approach compared to other microscopies, there was a lack of credibility and validation until now. However, this work shows that this technique is really powerful and flexible for studying living systems and their molecular components.

Q: Is there anything else yet to discover about the cell walls in Gram-positive bacteria?

Of course! That’s the best part. This was just the first door to open. There are many more questions in this field still to tackle. How do antibiotics affect the cell wall? What makes the antibiotic-resistant strain of bacteria different from the non-resistant ones? Could we apply this technique to other species?

We are currently working and trying to answer some of these questions, but this is a task that will require wider collaboration across different groups and countries. This is a new era for the study of bacterial cell walls. Everyone should join to speed up the race against antimicrobial resistance.

Q: So, where do you think this research should move into? What’s the future?

I think this is the beginning of a new way of doing research in Microbiology. Studying the changes in the morphology of the whole cell is no longer enough. If we really want to understand these complex cells, we need to look closer. If other groups join us, in the journey to study bacteria with Atomic Force Microscopy and other super-resolution microscopy techniques, we will make this the new normal. Our work shows that the key to moving forward in the future is interdisciplinary collaboration. In our case, physicists and microbiologists working together for almost two decades have made this possible. Other disciplines have not been involved in research on bacteria before, but maybe now they should.

Q: My last question is a bit more personal. How come a PhD Researcher from the Department of Physics and Astronomy ends up working with bacteria?

This is one of my favorite questions. Since I was in high school I had an equal interest in all things related to Biology and at the same time to Physics and Astronomy. I’ve wanted to be an astronomer since I was a kid. Hence, I decided to do Physics in my undergraduate. In the last two years of my undergraduate, my fascination with biophysics grew to the point I did a Masters specialising in Nanobiotechnology in Barcelona. In my Master’s project, I discovered Atomic Force Microscopy and I thought that applying this technology to solve a biological problem would be ideal for my future career.

Then, when I was looking for PhDs, I saw an offer from Jamie Hobbs’ (Professor at the Department of Physics and Astronomy) group to precisely apply this technique to bacteria and I knew this was my ideal place. I couldn’t be happier when I got accepted and I’ve spent the last three and a half years learning as much Microbiology as I could and perfecting my skills. As a physicist, I love doing quantitative analysis. This is why we applied it as much as we could to our work on this paper. You could say that this project was “specifically designed” for me because it has been the perfect fit for both of my passions. I truly enjoyed doing my PhD in Sheffield and being part of this amazing collaborative environment.

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