The enigmatic LiaXYZ System of Enterococcus faecalis and its role in resistance to cell envelope-targeting antibiotics

• Applicant: Professorin Susanne Gebhard, Ph.D.
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563781271

Enterococci are responsible for about 10% of hospital acquired infections. Such infections are hard to treat, because the bacteria are resistant against many antibiotics, particularly those that target the cell envelope, leading to high mortality rates. One of the most promising antibiotics for treating drug-resistant enterococci is daptomycin. This drug works by disrupting the bacterial cell wall and cellular membrane, killing the bacteria. However, enterococci are already starting to become resistant to daptomycin. Understanding how this resistance works is critical for better treatments. It has been found that resistance to daptomycin often involves changes in a regulatory system in the bacteria called LiaFSR. These changes strongly switch on several genes, including a group coding for the three proteins LiaX, LiaY and LiaZ. This study aims to unravel how the LiaXYZ system works in E. faecalis and how it protects the bacterium from daptomycin and other antibiotics. Our research so far has led us to the hypothesis that LiaX helps to protect the bacteria from daptomycin by preventing membrane damage or by allowing cell wall production to continue. LiaY probably interacts with LiaX, helping to control where it is situated in the cell or the membrane. For LiaZ we know very little so far. It may work by destroying some cells of the population, but how this could contribute to antibiotic resistance is not clear. In this project, we will use genetic and biochemical techniques to understand exactly how much each of the three proteins contributes to daptomycin resistance. We will fuse the proteins to fluorescent markers to track them in the cell and see how their behaviour changes when the antibiotic is present. We will also investigate how LiaX interacts with membranes and with itself. And finally, we will test how LiaZ’s activity helps to protect the bacteria. Overall, this research could help develop better strategies to fight antibiotic-resistant bacteria.

• DFG Programme: Research Grants