Targeting bacterial defense mechanisms for effective antibiotic treatment

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In addition to the urgent need for new antibiotics, alternative strategies are required to tackle the problem of antibiotic resistance. Michaela Wenzel, Associate Professor at Chalmers University of Technology, is investigating bacterial defenses against external stress to make these a target for efficient antibiotic treatments.

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.

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 is an ideal target for treatments

The bacteria's primary defense 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," 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."

Finding 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 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 unfavorable 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. The team has published a paper on this topic in Nature Communications.

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 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 Wenzel's group received a 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."

More information: Declan A. Gray et al, Membrane depolarization kills dormant Bacillus subtilis cells by generating a lethal dose of ROS, Nature Communications (2024). DOI: 10.1038/s41467-024-51347-0

Journal information: Nature Communications

Provided by Chalmers University of Technology