Bacterial defence mechanisms targeted for treatment

When addressing the problem of antibiotic resistance, Michaela Wenzel highlights that globally, many lives could be saved with measures already practiced in Sweden. These include access to clean water, improved hygiene, and restrictions on antibiotic use in agriculture − but this alone is not enough.

“We cannot stop bacteria from developing antibiotic resistance. It is evolution, and we will have to live with it. Of course, we need to find new substances that can act as antibiotics, but it is time-consuming and expensive. Therefore, we also need alternative strategies,” she says.

Michaela Wenzel is a microbiologist working at the Department of Life Sciences with a focus on bacterial cell biology. Her specific research interest is the molecular interaction between antibiotics and bacterial cells − examining what happens when antibiotics affect cells and how bacteria defend themselves.

The cell envelope an ideal target for treatments

The bacteria’s primary defence against their environment is an intact cell envelope, and changes to the envelope can be crucial for the cell's survival. This makes the cell envelope an ideal target for future treatments of bacterial infections.

“Various types of ß-lactam antibiotics such as penicillin, which kill bacteria by targeting the synthesis of the cell wall, are among the most common treatments today. However, as resistance is rising, we need new ways to target the vital cell envelope,” Michaela Wenzel explains.

To understand how antibiotics affect different components of the cell envelope or how bacteria respond to antibiotics her group uses and develops advanced microscopy techniques combined with spectroscopy and various omics technologies (large-scale analysis of genes, proteins, or other selected molecules in cells)

“The cell envelope is both very well-studied and at the same time horribly understudied. There are certain things that we just cannot measure in living bacterial cells and artificial models will never truly capture the complexity of the living system. We are trying to develop and adapt methods to study these cell envelope parameters in living bacterial cells in real time and super resolution.”

Aim to find molecules that alter membrane channels

The research team runs several parallel projects investigating protective stress mechanisms found in all bacteria, unrelated to evolutionary development of resistance, aiming to identify ways to disable them. One focus is on membrane channels in the cell envelope that transport molecules out of the cell.

These channels' natural function is to release molecules from the cell upon hypoosmotic stress (adjustment to low-salt environments). Antibiotics targeting the cell envelope trigger the same response. Blocking the channel makes the bacteria more sensitive to antibiotics. At the same time, specific classes of antibiotics can hijack the channels when they are open and use them to enter the cells. Substances that act as either inhibitors or activators of these channels could therefore be useful, depending on the antibiotic used.

“We aim to find molecules that can alter channel function, either to inhibit or activate the channel. The strategy is to use these molecules alongside different groups of existing antibiotics to maximize their effect. This approach will act as a combination therapy where the choice of antibiotic determines whether we activate or block the channel,” says Michaela Wenzel.

Collaborative project focused on dormant bacteria

The research team is also part of a collaborative project focused on so-called non-growing cells. Some bacteria can enter a dormant state under unfavourable conditions, shutting down their metabolism. In this state, the cells are resistant to antibiotics and difficult to treat, often causing latent and recurring infections such as tuberculosis.

To kill non-growing cells, antibiotics must target cellular structures that are essential for survival, rather than metabolic processes. It is already known that several common antibiotics that block bacterial DNA or protein synthesis also increase the production of reactive oxygen species. These toxic radicals enhance the effect of the antibiotics.

“In the study, we examined how antibiotics that affect the membrane of dormant bacteria kill the cells. We discovered a new mechanism where disruption of bacterial respiration leads to increased production of a reactive oxygen species, superoxide, which in turn causes cell death,” says Michaela Wenzel.

New approaches to fight fungal infections

Collaborations in research projects are particularly important to her. It contributes not only to her development as a scientist but also to advancing research and strategies against antibiotic resistance through interdisciplinary efforts.

In November 2024, a consortium including the group of Michaela Wenzel received a JPIAMR grant, addressing the increasing problem with resistance to antifungal drugs and calling for new approaches to combat fungal infections. 

“The grant supports an interdisciplinary and international consortium aiming to develop metal compounds to combat various fungal infections. This is the first time my research group is specifically focusing on fungi, so we have a very exciting time ahead of us.”

"Interdisciplinary interactions our greatest strength"

In addition to being a research leader, Michaela Wenzel serves as deputy director of the Centre for Antibiotic Resistance Research in Gothenburg (CARe), a collaboration between Chalmers, the University of Gothenburg, Sahlgrenska University Hospital, and the Västra Götaland Region, involving over 150 researchers. CARe facilitates and supports research collaborations and acts as an advisor to both the government and the UN's Environment Programme (UNEP). It actively participates in educational projects, such as activities for school children.

“Here, we have interdisciplinary interactions between researchers from very different fields − social sciences, environment, ethics, mathematics, and biology. To me, that is our greatest strength. We don’t look at the problem solely from a medical perspective. The focus is on bringing people together, and now we have a platform for “out of the box” collaborations that might never have otherwise occurred. We also contribute to a clear and comprehensive understanding of the current situation,” Michaela Wenzel concludes.

Michaela Wenzel about:

Becoming a researcher

“I have always wanted to become a researcher. Even as a child, I had a toy microscope and examined everything I could get my hands on. Then I watched the movie Outbreak and started to collect data about infectious diseases. I had a lab coat and test tubes and pretended to be a scientist finding a cure to contagious diseases.”

What motivates her in her work

“I love the flexibility in an academic role. Sometimes the focus is more on research projects, other times on teaching, outreach activities for schools and the public, or engaging in contexts where you can influence policymakers. All this fits into one single role, and I get to enjoy a varied workday without needing to change jobs. At 19, I said I wanted a job that didn’t involve doing the same thing every day – because that was my biggest fear – and now I’m exactly where I want to be.”

Persistence as a driving force

“During my PhD, I studied how antibiotics interact with bacterial membranes, but at the time, there were no methods available to investigate the specific mechanisms I was looking at. When I hit a wall – that was when the subject became truly interesting to me. Despite, or perhaps because of, being advised not to continue, I ran a few more experiments – and they led to the discovery of a previously unknown mechanism. It was a true "aha" moment and confirmation that I was right to take a different path.”

Writing research grant applications

“I think the process is similar to the games I played as a child when I created freely out of my imagination, building worlds with LEGO. I have my basic framework, but I am free to choose which path to take, what structure to build and what to fill it with. I enjoy this part of being a researcher, planning and determining the direction of my research.”

The importance of collaboration

“I genuinely want to collaborate with people who can see and understand things beyond what I can perceive. I am no Einstein – I really don’t know everything – and I need others’ perspectives on things I can’t grasp. I’m currently starting an exciting collaboration on deep-sea bacteria, and I am just as thrilled as I was when I first watched Outbreak.”