Michaela Wenzel’s group studies the molecular mechanisms of antibiotic action and resistance in living bacteria with a focus on the cell envelope. The major the aim is to improve the fundamental knowledge of how antibiotics interact with bacterial cells, which is pivotal to develop more sustainable antibiotics and novel antibacterial strategies.
The antibiotic resistance crisis
The discovery of antibiotics, heralded by compounds like salvarsan, penicillin, and gramicidin, revolutionized modern medicine and formerly deadly diseases became easily treatable. However, this privileged situation could change drastically over the next years. Bacteria possess a remarkable genetic capability to adapt and become resistant to existing antibiotics.
Only few new antibiotics have been developed in the past decades, which makes it increasingly difficult to keep up with the emergence of resistant bacteria. To prevent a fallback into a pre-antibiotic era, we need to advance antibiotic discovery and minimize the development and spread of antibiotic resistance.
The bacterial cell envelope
The key to antibiotic sustainability is to develop substances that leave little possibility for bacteria to adapt and become resistant too fast. One strategy to achieve this is to target the bacterial cell envelope. This complex structure, which consists of one or two lipid membranes and a cell wall composed of sugars and amino acids, separates the cell from the outside environment.
An intact cell envelope is essential for bacteria to survive, and its complexity largely precludes spontaneous resistance mutations. Moreover, changes in cell envelope structure are often poorly tolerated, which leaves less room for bacteria to develop resistance.
Antibiotics that impair cell envelope functions, such as penicillin, are very successful in treating infections. However, only a tiny fraction of possible cell envelope targets is currently exploited, leaving plenty of unused potential.
Identification of new antibiotic targets
To exploit this promising antibiotic target structure more successfully, it is necessary to first understand how antibiotics interfere with it and what measures bacteria have to adapt their cell envelopes to antibiotic exposure. Surprisingly little detail is known about these mechanisms, especially considering that the first antibiotics were discovered over a century ago. Recent advances in microscopy technologies have opened up a whole new dimension to study formerly inaccessible details.
In Michaela Wenzel’s lab a combination of live single-cell fluorescence imaging, high-resolution fluorescence and electron microscopy, spectroscopy, and -omics techniques are used to elucidate the mechanisms underlying antibiotic action and resistance to better understand how the cell envelope can be targeted by future antibiotics. The long-time goal of this research is to identify promising new antibiotic targets within the bacterial cell envelope and to develop strategies to target bacterial adaptation and resistance systems with the aim to re-sensitize resistant bacteria to existing antibiotics (=antibiotic adjuvants).
Michaela Wenzel’s group characterizes potential new antibiotic and adjuvant targets and develops and characterizes potential inhibitors of those. In addition to the cell envelope, the group studies DNA and DNA-binding proteins as antibiotic targets and performs mode of action analysis of new compounds of unknown function.
