Targeting bacterial defense mechanisms for effective antibiotic treatment

In addition to the urgent need for new antibiotics, alternative strategies are also needed to tackle the problem of antibiotic resistance. Associate Professor Michaela Wenzel of Chalmers University of Technology studies bacterial defenses against external stress and targets these for efficient antibiotic treatments.

Michaela Wenzel emphasizes that the measures already in place in Sweden could save lives globally when tackling the problem of antibiotic resistance. These include access to clean water, improved sanitation and limiting the use of antibiotics in agriculture, but this alone is not enough.

“We can’t stop bacteria from acquiring antibiotic resistance. This is evolution and we have to live with it. Of course we need to find new substances that act as antibiotics. But that takes time and money. So we also need alternative strategies,” she says.

Wenzel is a microbiologist in the School of Life Sciences specializing in bacterial cell biology. Her special research interest is in the molecular interactions between antibiotics and bacterial cells, studying what happens when antibiotics affect cells and how bacteria defend themselves. .

The cell envelope is an ideal target for therapy

The main defense of bacteria against the environment is the intact cell envelope, and changes in the envelope can be important for cell survival. This makes the cell envelope an ideal target for future treatment of bacterial infections.

“Various types of beta-lactam antibiotics, such as penicillin, which kill bacteria by targeting cell wall synthesis, are the most common treatments today. “We need new ways to target it,” Wenzel explains.

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

“The cell envelope is both extremely well-studied and woefully understudied. There are some things that cannot be measured in living bacterial cells, and artificial models cannot truly capture the complexity of living systems. We are trying to develop and adapt a method to study these cell envelope parameters in living bacterial cells in real time and with super-resolution. ”

Discovery of molecules that change membrane channels

The research team is running multiple parallel projects investigating defensive stress mechanisms found in all bacteria, unrelated to the evolutionary development of resistance, with the aim of identifying ways to neutralize them. One focus is on membrane channels within the cell envelope that transport molecules out of the cell.

The primary function of these channels is to release molecules from cells during hypoosmotic stress (adjustment to a low-salinity environment). Antibiotics that target the cell envelope cause the same response. Blocking the channel makes bacteria more susceptible to antibiotics. At the same time, certain types of antibiotics can hijack the channels when they are open and use them to enter cells. Therefore, depending on the antibiotic used, substances that act as inhibitors or activators of these channels may be useful.

“We aim to find molecules that can inhibit or activate channels, changing their function. The strategy is to use these molecules in conjunction with different groups of existing antibiotics. , to maximize its effectiveness. This approach works as a combination therapy. The antibiotic determines whether it activates the channel or blocks it,” says Wenzel.

Collaborative project focused on dormant bacteria

The research team is also involved in a joint project focusing on so-called non-proliferating cells. Some bacteria can enter a dormant state and stop their metabolism under unfavorable conditions. In this condition, cells are resistant to antibiotics, difficult to treat, and often result in latent or recurrent infections such as tuberculosis. The research team published a paper on this topic in the journal Nature Communications.

To kill cells that are not proliferating, antibiotics must target cellular structures essential for survival rather than metabolic processes. It is already known that some common antibiotics that block bacterial DNA or protein synthesis also increase the production of reactive oxygen species. These toxic radicals increase the effectiveness of antibiotics.

“In this study, we investigated how antibiotics that affect the membranes of dormant bacteria kill cells. When bacterial respiration is inhibited, production of superoxide, a reactive oxygen species, increases. “We discovered a new mechanism by which it causes cell death,” says Wenzel.

A new approach to fighting fungal infections

Collaboration on research projects is especially important to her. It will not only contribute to her growth as a scientist, but also to the advancement of research and strategies against antibiotic resistance through interdisciplinary efforts.

In November 2024, a consortium including Wenzel’s group received a grant to address the growing problem of resistance to antifungal drugs and call for new approaches to combating fungal infections.

“This grant will support an interdisciplinary international consortium aimed at developing metal compounds to combat a variety of fungal infections. This is the first time my research group has focused specifically on fungi. There are very exciting times ahead.”