A novel player in persistence: How protein aggregation allows bacteria to survive antibiotic treatment

Recently, we are realizing that bacterial infections become more and more threatening because of the development of antibiotic resistance. Moreover, even infections with sensitive bacteria are often difficult to eradicate due to the presence of so-called persisters, dormant bacteria that are temporarily tolerant to treatment with antibiotics. The physiology of these persisters, together with their entry and exit from the dormant state, remains fragmentary at best. However, in-depth understanding of this clinically-relevant phenomenon could greatly improve treatment strategies and outcomes. We therefore propose to investigate bacterial dormancy in more detail. In this analysis, not only the persister cells, but also other dormant cells like VBNCs are studied. We will focus on the role of protein aggregation in inducing dormancy and persistence. An important role for protein aggregation in the onset of dormancy and persistence has recently been suggested. However, any mechanistic insight is currently lacking. Our research will greatly extend the current state-of-the-art by revealing how aggregation leads to dormancy, which regulatory mechanisms control protein aggregation and how cells can exit the dormant state to resume growth and reestablish infections. Analysis will be based on protein overexpression, high-throughput CRISPR analysis and single cell studies using the mother machine. Insights gained will not only be of great value for our fundamental understanding of cellular dormancy, but can also serve as a starting point for the development of antipersister therapies.